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Ray Peat, PhD on the Menstrual Cycle

Also see:
Light is Right
Hot flashes, energy, and aging
SOS for PMS
Collection of Ray Peat Quote Blogs by FPS
Progesterone Decreases Aromatase Activity
Quotes: Thyroid, Estrogen, Menstrual Symptoms, PMS, and Infertility
Estrogen Stimulates Insulin, Promotes Weight Gain
Possible Indicators of Excess Estrogen
Progesterone: Essential to Your Well-Being
Plasma Estrogen Does Not Reflect Tissue Concentration of Estrogen
Estrogen and PCOS
Shock Increases Estrogen
Autoimmune Disease and Estrogen Connection
Hormonal profiles in women with breast cancer
PUFA Increases Estrogen
PUFA Inhibit Glucuronidation
PUFA Promote Cancer
Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring
Vitamin A: Anti-Cancer and Anti-Estrogen
Toxic Plant Estrogens
The Dire Effects of Estrogen Pollution
Alcohol Consumption – Estrogen and Progesterone In Women
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Estrogen Levels Increase with Age
Fat Tissue and Aging – Increased Estrogen
Estrogen Related to Loss of Fat Free Mass with Aging
Bisphenol A (BPA), Estrogen, and Diabetes
PUFA, Estrogen, Obesity and Early Onset of Puberty
Estrogen Related to Loss of Fat Free Mass with Aging
Nutrition and Brain Growth in Chick Embryos
The Brain: Estrogen’s Harm and Progesterone’s Protection
Estrogen Increases Serotonin
Estrogen, Serotonin, and Aggression
Women, Estrogen, and Circulating DHA
PUFA, Fish Oil, and Alzheimers
Estrogen, Glutamate, & Free Fatty Acids
Phospholipases, PUFA, and Inflammation
Estrogen’s Role in Seizures
Benefits of Aspirin
Estrogen’s Role in Asthma
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)

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“Women’s monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be involved in the regulation of cell renewal.”

“Cells respond to stimulation by estrogen by producing a variety of molecules, including the “progesterone receptor” protein. When progesterone enters the cell, binding to these proteins, the estrogenic stimulation is halted, by a series of reactions in which the estrogen receptors disintegrate, and in which estrogen is made water soluble by the activation of enzymes that attach sulfate or a sugar acid, causing it leave the cell and move into the bloodstream, and by reactions that prevent its reentry into the cell by inactivating another type of enzyme, and that suppress its de novo formation in the cell, and that oxidize it into a less active form. Progesterone terminates estrogen’s cellular functions with extreme thoroughness.”

“In polycystic ovaries, menopausal symptoms, arthritis, angina pectoris, multiple sclerosis, some kinds of dementia, migraine, and emphysema, the relief achieved with a simple improvement of cellular energy can be rapid and complete.”

“For example, the follicular phase is a time of low steroid production by the ovary, until near the end of the phase, just before ovulation, when estrogen rises. The luteal phase is a time of high estrogen and high progesterone synthesis. Many publications describe the follicular phase as a time of high estrogen, and the luteal phase as a time of low estrogen, roughly the opposite of the actual situation. And an even larger number of studies get the results they want by using a short exposure to estrogen to study something which takes a long time to develop.”

“The normal cyclic function of the ovaries is a model for the potentially creative role of an inflammation-like stress. Every month (in a rhythm influenced by many cues), a productive crisis comes to a focus in the ovary, with the formation of estrogen, prostaglandins, carbon monoxide, and other signal substances, causing rapid changes both locally and systemically, with water, hormones, and nutrients gathering around the ovum (as well as in other parts of the body, such as the feet). Then as the follicle ruptures with the release of an ovum, the excitatory, inflammation-like state is resolved, with a massive increase in the production of antiinflammatoy, antistress substance, progesterone, leading to the suppression of the excitatory substances. These monthly processes are developmental, they are part of the epigenetic development of the organ.

Most, if not all, of the substances involved in ovarian physiology are involved in the disease of stress and degeneration, which progress in proportion to the inability to produce the resolution of inflammation and restoration of the stable condition. The ovary is a major source of estrogen which can produce the excited, activated, inflammatory, and proliferative state in any tissue of the body, though it acts mainly on the uterus, breasts, and pituitary. But the ovary is also, in response, able to produce massive amounts of the protective progesterone, which interrupts the inflammatory effects of estrogen on the various tissues and organs, largely by suppressing the proteins that hold estrogen within cells (especially the “estrogen receptor”), but also by changing the activities of many enzymes away from the estrogen-controlled, inefficient pattern. The developmental actions of the ovary cause continuing epigenetic process in other organs, causing noticeable changes in their structure every month.”

“The estrogen dominance which is needed to start the reproductive cycle, with cell proliferation in the endometrium, breast, and pituitary, is not otherwise useful to the organism, and is controlled and opposed during pregnancy by a constantly rising production of progesterone. The state of estrogen dominance is essentially unstable.”

“Minks that have mated in the winter don’t implant the fertilized ovum in the uterus until the spring equinox, when progesterone rises suddenly, and allows both the uterus and the embryo to begin the process of pregnancy and gestation. Progesterone provides the oxygen needed for the successful implantation of the embryo, while estrogen and serotonin lower the intrauterine oxygen.

Under good conditions, the (premenstrual) luteal phase of the monthly cycle resembles pregnancy, as a period of progesterone dominance, in which the abundance of progesterone causes cells to decrease their estrogen content. The luteal phase is actually the first stage of pregnancy, and if there is implantation of an embryo all of the processes that begin at ovulation progress continuously until childbirth occurs. When there is no implantation, the luteal phase progesterone dominance is terminated, allowing estrogen to enter tissues and producing menstruation. The sudden decrease of progesterone production before menstruation is similar to the decrease of hormone production just before childbirth. The same conditions that produce the premenstrual syndrome, if they aren’t corrected by the placenta’s massive production of progesterone, will produce preeclampsia, toxemia of pregnancy, eclampsia, and postpartum depression. They are also related to the problems that become so common at menopause. Whenever the production of progesterone falls, tissues are susceptible to estrogen.

There are several common causes of a progesterone deficiency. Deficiencies of thyroid, vitamin A, and cholesterol are often responsible for a progesterone deficiency. Inadequate light exposure can cause it. Excess polyunsaturated fats, interfering with gonads and thyroid, can cause it. And excess serotonin can cause it.”

“In the ovary and uterus, the healthy alternation of excitation and quiescence usually continues for many years, and in rodents it often ends in a state of “persistent estrus,” in which the excitatory state can’t be terminated in the usual way, by the production of progesterone. In humans, menopause is analogous, because the excitatory FSH hormone from the pituitary becomes excessive, with the ovary continuing to produce estrogen but failing to produce progesterone, sometimes with the pituitary failing to shift from FSH to LH. In rodents, it’s recognized that persistent estrus is caused by chronically elevated estrogen, but in humans there has been tremendous resistance to the recognition of estrogen’s central role in menopause and senescence. An excess of the basic promoter of inflammation, serotonin, which is closely associated with estrogen’s influence, can have similar effects on the reproductive cycle (Cooper, et al., 1986). The industry has devoted the necessary funding to making the easily manipulated medical culture, and the public, believe the opposite, i.e., that reproductive aging is mainly caused by estrogen deficiency.”

“Stress uses progesterone and can cause menstrual periods to stop. Girls who begin regular exercise (such as dancing) before puberty have later sexual development.”

“Stress, trauma, and shock start an inflammatory process, that can cause progressive damage to the organs, including the liver. Giving progesterone following the injury protects against the increase of TNF, IL-6, and leakage of liver enzymes (Kuebler, et al., 2003). It has similar protective effects in the brain, lungs, and other organs. During the normal menstrual cycle, IL-6 is inversely related to the level of progesterone (Angstwurm, et aI., 1997).”

Dr. Peat’s (Progesterone) Dosage Recommendations
For topical treatment of sun damaged skin, or acne, wrinkles, dark marks, the oil can be applied directly to the affected areas.

Since progesterone has none of the harmful side effects of other hormones (except the alteration of the menstrual cycle if taken at the wrong time of the month), the basic procedure should be to use it in sufficient quantity to make the symptoms disappear, and to time its use so that menstrual cycles are not disrupted. This normally means using it only between ovulation and menstruation unless symptoms are sufficiently serious that a missed period is not important to you.

If a person has an enlarged thyroid gland, progesterone encourages secretion and unloading of the stored colloid and can bring on a temporary hyperthyroid state which is a corrective process. A thyroid supplement, like Thyodine may be used to shrink the goiter before progesterone is given.

Normal amounts of progesterone promote thyroid secretion, while a deficiency, especially when too much estrogen is present, causes the thyroid to enlarge. Some mention euphoria as a “side-effect” of progesterone usage, but euphoria is simply an indication of good physiological state. To avoid unexpected anesthesia, the correct dose should be determined by taking about 10 mg (3-4 drops) at a time, allowing it to spread into the membranes of the mouth, and repeating the dose after 10 minutes until the symptoms are controlled.

An excessive estrogen/progesterone ratio (should be 1 part to 10 parts, estrogen to progesterone), is involved in producing aggravating symptoms such thin, bluish skin. Low thyroid is one cause of excess estrogen, and when high estrogen is combined with low thyroid function, the skin can look relatively bloodless.

Symptoms in cycling women are most common around ovulation and in the premenstrual week, when the estrogen/progesterone ratio is normally highest. At puberty, in the early twenties and in the late thirties and menopause are the ages when the ratio is most often disturbed – and these are also the ages when thyroid disorders are most common.

The individual who suffers from one aspect of progesterone (and/or thyroid) deficiency will tend to develop other problems at varying times. With cyclic depression or migraine headaches at 22, there will possibly be breast disease after, and often there will be problems with pregnancy. These people with a history of severe symptoms are the ones most likely to have problems around menopause. Prenatal exposure to poorly balanced hormones seems to predispose children to later hormone imbalances.

Excess stress (which can block progesterone synthesis and elevate estrogen) may being on symptoms in someone who never had them. As well as darker days without sun, toxins and nutritional deficiencies. A very common cause of an estrogen excess is a dietary protein deficiency because the liver cannot detoxify estrogen when it is under nourished.

With a diet high in protein and vitamin A, progesterone can usually be reduced each month. Using thyroid supplementation will also usually reduce the amount of progesterone needed. Occasionally, a women won’t feel any effect even from 100 mg of progesterone and this may indicate they need to use thyroid supplementation and diet changes to normalize their estrogen, prolactin and cortisol levels.

Progesterone stimulates the ovaries and adrenals to produce progesterone, and it also activates the thyroid. It shouldn’t be necessary to use progesterone indefinitely unless the ovaries have been removed. In slender post-menopausal women, 10 mg per day is usually enough to prevent progesterone deficiency.

Ina 10% solution of progesterone in vitamin E, one drop contains about three milligrams of progesterone. Normally the body produces 10 to 20 milligrams per day. A dose of 3 or 4 drops usually brings the blood levels up to normal range, but this dose can be repeated throughout the day to control symptoms.

For general purposes, it is most economical and effective to take progesterone dissolved in vitamin E orally, for example taking a few drops on the lips and tongue, or rubbing it into the gums. (It is good for the general health of the gums, too.) These membranes are very thin and hence the progesterone can easily and quickly enter the blood. when swallowed, the vitamin E allows it to be absorbed through the walls of the stomach and intestine.

As was mentioned previously, topical application of this oil aids sun damaged skin. For topical treatment of arthritis, osteoporosis, tendinitis, bursitis, or varicose veins, to speed absorption it is best to apply a few drops of olive oil to the area, and then to rub the progesterone -vitamin E solution into and around the affected area.”

PROGESTERONE SUPPLEMENTATION
SYMPTOMATIC: For tendonitis, bursitis, arthritis, sunburn, etc., progesterone in vitamin E can be applied locally after a little olive oil has been put on the skin to make it easier to spread the progesterone solution. For migraines, it has been taken orally just as the symptoms begin.

FOR PMS: The normal pattern of progesterone secretion during the month is for the ovaries to produce a large amount in the 2nd two weeks of the menstrual cycle, (i.e., day 14 through day 28) beginning at ovulation and ending around the beginning of menstruation, and then to produce little for the following two weeks. An average person produces about 30 milligrams daily during the 2nd two weeks. The solution I have used contains approximately 3 or 4 milligrams of progesterone per small drop. Three to four drops, or about 10 to 15 milligrams of progesterone, is often enough to bring the progesterone level up to normal. That amount can be taken days 14 through 28 of the menstrual cycle; this amount may be repeated once or twice during the day as needed to alleviate symptoms. Since an essential mechanism of progesterone’s action involves its opposition to estrogen, smaller amounts are effective when estrogen production is low, and if estrogen is extremely high, even large supplements of progesterone will have no clear effect; in that case, it is essential to regulate estrogen metabolism, by improving the diet, correcting a thyroid deficiency, etc. (Unsaturated fat is antithyroid and synergizes with estrogen.)

PERIMENOPAUSAL: The symptoms and body changes leading up to menopause are associated with decreasing production of progesterone, at a time when estrogen may be at a lifetime high. The cyclic use of progesterone, two weeks on, two weeks off, will often keep the normal menstrual cycle going. Three to our drops, providing ten or twelve milligrams of progesterone, is typical for a day, but some women prefer to repeat that amount. Progesterone is always more effective when the diet contains adequate protein, and when thee isn’t an excessive amount of unsaturated fat in the diet.

POSTMENOPAUSAL: Some women continue the cyclic use of progesterone ater menopause, because the pituitary gland and brain may continue to cycle long after menstruation has stopped, and progesterone is an important regulator of pituitary and brain function. The cycling pituitary affects the adrenal glands and other organs, and progesterone tends to protect against the unopposed actions of prolactin, cortisol, and adrenal androgenic hormones. Progesterone’s effects on the pituitary apparently contribute to its protective effect against osteoporosis, hypertension, hirsutism, etc. But some women prefer to use progesterone without interruption after the menopause, for its protective antistress effects. Slender people usually find that two or three drops are enough, but this amount may be repeated once or twice as needed to relieve symptoms. Adequate protein in the diet and good thyroid function help the body to produce its own progesterone; even if the ovaries have been removed, the adrenal glands and brain continue to produce progesterone.

DOSAGE OF PROGESTERONE
Since progesterone has none of the harmful side effects of other hormones (except for alteration of the menstrual cycle if it is taken at the wrong time of month), the basic procedure should be to use it in sufficient quantity to make the symptoms disappear, and to time its use so that menstrual cycles are not disrupted. This normally means using it only between ovulation and menstruation unless symptoms are sufficiently serious that a missed period is not important. The basic idea of giving enough to stop the symptoms can be refined by some information on a few of the factors that condition the need for progesterone.

An excessive estrogen/progesterone ratio is more generally involved in producing or aggravating symptoms than either a simple excess of estrogen or a deficiency of progesterone, but even this ratio is conditioned by other factors, including age, diet, other steroids, thyroid, and other hormones. The relative estrogen excess seems to act by producing tissue hypoxia (as reported in my dissertation, University of Oregon, 1972), and this is the result of changes induced by estrogen in alveolar diffusion, peripheral vascular changes, and intracellular oxygen wastage.

Hypoxia in turn produces edema (as can be observed in the cornea when it is deprived of oxygen, as by a contact lens) and hypoglycemia (e.g., diminished ATP acts like insulin), because glycolysis must increase greatly for even a small deficiency of oxygen. Elevated blood lactic acid is one sign of tissue hypoxia. Edema, hypoglycemia, and lactic academia can also be produced by other “respiratory” defects, including hypothyroidism, in which the tissue does not use enough oxygen. In hypoxia, the skin will be bluer (in thin places, such as around the eyes), than when low oxygen consumption is the main problem. Low thyroid is one cause of excess estrogen, and when high estrogen is combined with low thyroid, the skin looks relatively bloodless.

Symptoms in cycling women are most common around ovulation and in the premenstrual week, when the estrogen/progesterone ratio is normally highest. At puberty, in the early twenties and in the late thirties and menopause are the ages when the ratio is most often disturbed–and these are also the ages when thyroid disorders are commonest in women.

The individual who suffers from one aspect of the progesterone (and/or thyroid) deficiency will tend to develop other problems at different times. With cyclic depressions or migraine headaches at age 22, there will possibly be breast disease later, and often there will be problems with pregnancy. These people with a history of sever symptoms are the ones most likely to have severe problems around menopause. Prenatal exposure to poorly balanced hormones seems to predispose the child to later hormone problems.

Excess stress (which can block progesterone synthesis and elevate estrogen) may bring on symptoms in someone who never had them. Spending a summer in Alaska, with an unusually long day, may relieve the symptoms of a chronic sufferer. Dark cloudy winters in England or the Pacific Northwest are powerful stressors, and cause lower production of progesterone in women, and testosterone in men. Toxins can produce similar symptoms, as can nutritional deficiencies. A very common cause of an estrogen excess is a dietary protein deficiency–the liver simply cannot detoxify estrogen when it is under-nourished.

With a diet high in protein (e.g., at least 70-100 grams per day, including eggs) and vitamin A (not carotene), I have found that the dose of progesterone can be reduced each month. Using thyroid will usually reduce the amount of progesterone needed. Occasionally, a woman won’t feel any effect even from 100 mg. of progesterone; I think this indicates that they need to use thyroid and diet, to normalize their estrogen, prolactin, and cortisol.

Progesterone stimulates the ovaries and adrenals to produce progesterone, and it also activates the thyroid, so one dose can sometimes have prolonged effects. It shouldn’t be necessary to keep using progesterone indefinitely, unless the ovaries have been removed. In slender post-menopausal women, 10 mg. per day is usually enough to prevent progesterone deficiency symptoms.

In a 10% solution of progesterone in vitamin E, one drop contains about three milligrams of progesterone. Normally, the body produces 10 to 20 milligrams per day. A dose of 3 or 4 drops usually brings the blood levels up to the normal range, but this dose can be repeated several times during the day if it is needed to control symptoms.

For general purposes, it is most economical and effective to take progesterone dissolved in vitamin E orally, for example taking a few drops on the lips and tongue, or rubbing it into the gums. (It is good for the general health of the gums.) These membranes are very thin, and the progesterone quickly enters the blood. When it is swallowed, the vitamin E allows it to be absorbed through the walls of the stomach and intestine, and it can be assimilated along with food, in the chylomicrons, permitting it to circulate in the blood to all of the organs before being processed by the liver. These droplets are smaller than red blood cells, and some physicians seem to forget that red blood cells pass freely through the liver.

For the topical treatment of sun damaged skin, or acne, wrinkles, etc. the oil can be applied directly to the affected area.”

“I have observed the use of progesterone transdermally (applied to the skin in about 400 women suffering from the full range of peri-menstrual symptoms, including migraine, acne, depression, mastalgia (breast pain), edema (water retention and swelling), and lethargy. I found that nearly all the women who apply the lotion themselves, are able to find the appropriate dosage for controlling their symptoms. Occasionally, thyroid therapy, weight reduction: or change in some aspect of lifestyle is necessary for complete relief from symptoms. When some women said the progesterone had no effect, it turned out that they were applying it as sparingly as they would a rare perfume-just touching it to their wrists.

Anesthesia (or drunkenness) from a very large overdose is the only negative side effective reported in the literature. Experimenting with very large doses of natural progesterone on myself, for migraine, I found that there is a temporary antagonism to testosterone, causing small symptoms, including a slight sense of gregariousness, an urge to socialize. However, synthetic progestins do have harmful side effects including breast tumors. Unfortunately, most physicians do not yet know the difference between natural progesterone and synthetic progestins.”

“Estrogen’s name, derived from the gadfly, accurately suggests its role as an excitant, getting things started. Progesterone’s name, relating to pregnancy, is compatible with thinking of it as an agent of calming and fulfillment. But these properties show up in every aspect of physiology, and the special cases of female estrus and pregnancy can be properly understood only in the larger context, in which, for example, progesterone is a brain hormone in both sexes and at all ages, and estrogen is an essential male hormone involved in the sperm cell’s function and male libido.”

“Sometimes progesterone can cause an underactive enlarged thyroid gland to begin secreting, temporarily producing mild hypothyroidism while the gland returns to a normal size. Supplemental progesterone can reduce excessive cortisol production.

Since progesterone helps the thyroid to secrete, and helps the liver to regulate glucose and convert T4 to T3, women who are low in progesterone usually have hypothyroid symptoms (because of insufficient T3), including high cortisol, which promotes the synthesis of estrogen (in several ways, but never from progesterone). Cortisol is made from progesterone, but increasing the supply of progesterone reliably lowers cortisol synthesis, acting on the brain, pituitary, and adrenal glands. Progesterone, by many mechanisms, including its antagonism to cortisol, lowers the amount of estrogen in cells (causing the estrogen-binding proteins to be degraded, inhibiting the enzymes that release estrogen from the sulfates and glucuronides, and activating the enzymes that detoxify estrogen). So I think the symptoms of increased estrogen and cortisol are the result of either extraneous ingredients in the creams, or from using it at the wrong time, for example, too early, triggering premature ovulation. Supplementing a small amount of T3, Cytomel or Cynomel, usually stops symptoms such as breast pain, irritability, and restless energy, in less than an hour.”

“(progesterone) Protection against hypoglycemia is probably the main mechanism. Diabetic mothers often have precocious children, if they aren’t damaged by drugs and irrational diets. Ten to 15 grams per pregnancy, at increasing dosage, seems to be the optimal amount, when there is some sign of excessive estrogen or unexpected toxemia.”

“In good health, an animal’s systems are designed so that certain tissues will be intensely but briefly stimulated by estrogen.”

“It [progest-e] can help with cramps, but it would probably take a lot; I think it’s better to use thyroid (including T3) to solve the basic problem, since it will let you regulate the balance between estrogen and progesterone, while allowing your cells to balance the minerals, retaining the magnesium needed to prevent cramping. Increasing your intake of all the main minerals, calcium, sodium, potassium, and magnesium usually helps in the short term, but the balance isn’t stable if your thyroid is low. Milk, orange juice, coffee (even decaffeinated coffee is a good source of magnesium), and well salted foods, support thyroid functions. Aspirin helps with thyroid function and mineral balance, even helps to prevent excessive estrogen production.”

“More recently, it has been discovered that progesterone inhibits the expression of the enzyme nitric oxide synthase while estrogen stimulates its expression. At the time of ovulation, when estrogen is high, a woman breathes out 50% more nitric oxide (“NO”) than men do, but at other times, under the influence of increased progesterone and thyroid, and reduced estrogen, women exhale much less NO than men do. (Nitric oxide is a free radical, and it decomposes’ into other toxic compounds, including the free radical peroxyrutnle} which damages cells, including the blood vessels, brain, and heart. Carbon dioxide tends to inhibit the production of peioxynitrile.)”

“When estrogen is given to an animal, it almost instantly causes capillaries to become leaky, allowing water to move out of the blood stream, and at the same time, estrogen causes cells to take up water. Both of these processes are the same as the early effects of oxygen deprivation. In the normal reproductive cycle, the surge of estrogen lasts only a few hours, and normal permeability is quickly restored by increasing progesterone. During those intermittent short exposures to estrogen, there isn’t a massive leakage of serum proteins into the tissues. During the time of estrogenic influence, all kinds of cells are influenced, with the excitatory equilibrium of nerve cells, glandular cells, and immune system cells being shifted, lowering the threshold of excitation, or prolonging the excited state.”

“Our body controls estrogen’s effects by decreasing excitation while increasing efficient energy production.”

“Estrogen’s survival value exists only in the context of a whole organism with multiple ways for limiting estrogen’s destabilizing actions. Estrogen’s harmful effects occur when our systems for opposing it fail.”

“Women and other mammals that are deficient in progesterone, and/or that have an excess of estrogen, have a higher than average incidence of cancer. Animal experiments have shown that administering progesterone could prevent cancer. Cells in the most cancer-susceptible tissues proliferate in proportion to the ratio of estrogen to progesterone. When the estrogen dominance persists for a long time without interruption, there are progressive distortions in the structure of the responsive organs–the uterus, breast, pituitary, lung, liver, kidney, brain, and other organs–and those structural distortions tend to progress gradually from fibroses to cancer.

As a result of the early studies in both humans and animals, progesterone was used by many physicians to treat the types of cancer that were clearly caused by estrogen, especially uterine, breast, and kidney cancers. But by the 1950s, the drug industry had created the myth that their patented synthetic analogs of progesterone were medically more effective than progesterone itself, and the result has been that medroxyprogesterone acetate and other synthetics have been widely used to treat women’s cancers, including breast cancer.

Unfortunately, those synthetic compounds have a variety of functions unlike progesterone, including some estrogenic and/or androgenic and/or glucocorticoid and/or antiprogesterone functions, besides other special, idiosyncratic side effects. The rationale for their use was that they were “like progesterone, only better.” The unpleasant and unwanted truth is that, as a group, they are seriously carcinogenic, besides being toxic in a variety of other ways. Thousands of researchers have drawn conclusions about the effects of progesterone on the basis of their experiments with a synthetic progestin.”

“Each type of cell and organ is subject to injury, and in some cases these injuries are cumulative. In the healthy liver, which stores glycogen, toxins can be inactivated, for example by combining with glucuronic acid, derived from the stored glucose. With injury, such as alcoholism combined with a diet containing polyunsaturated fats, the liver’s detoxifying ability is reduced. Even at an early stage, before there is a significant amount of fibrosis, the reduced activity of the liver causes estrogen to accumulate in the body. Estrogen’s valuable actions are, in health, exerted briefly, and then the synthesis of estrogen is stopped, and its excretion reduces its activity, but when the liver’s function is impaired, estrogen’s activity continues, causing further deterioration of liver function, as well as injury of nerves such as Desjardins described, and the systemic energy shifts and stress activations mentioned above.

Besides lowering the liver’s detoxifying ability, stress, hypoglycemia, malnutrition, hypothyroidism, and aging can cause estrogen to be synthesized inappropriately and continuously. With aging, estrogen begins to be produced throughout the body–in fat, muscles, skin, bones, brain, liver, breast, uterus, etc. Polyunsaturated fats are a major factor in the induction and activation of the aromatase enzyme, which synthesizes estrogen.

Increased synthesis of estrogen, with aromatase, and decreased excretion of it, by the liver and kidneys, are only two of the processes that affect the influence of estrogen during aging. Cellular stress (chemical, mechanical, hypoxemic, hypoglycemic [Clere, et al., 2012; Aguirre, et al., 2007, Zaman, et al., 2006, Saxon, et al., 2007; Tamir, et al., 2002; Briski, et al., 2010]) increases estrogen receptors (which activate CRH and the stress response). The presence of estrogen receptors means that estrogen will be bound inside cells, where it acts to modify those cells. Before estrogen can reach the liver to be inactivated, it must be released from cells. Ordinarily, the cyclic production of progesterone has that function, by destroying the estrogen-binding proteins. Progesterone also inhibits the aromatase which synthesizes estrogen, and shifts the activities of other enzymes, including sulfatases and dehydrogenates, in a comprehensive process of eliminating the presence and activity of estrogen. At menopause, when the ovary fails to produce the cyclic progesterone, all of these processes of estrogen inactivation fail. In the absence of progesterone, cortisol becomes more active, increasing aromatase activity, which now becomes chronic and progressive. The decrease of progesterone causes many other changes, including the increased conversion of polyunsaturated fatty acids to prostaglandins, and the formation of nitric oxide, all of which contribute to the tendency to flush.”

“During the reproductive years, women’s cyclic production of large amounts of progesterone probably retards their aging enough to account for their greater longevity. Childbearing also has a residual antiestrogenic effect and is associated with increased longevity.”

“Estrogen blocks the release of hormone from the thyroid gland, and progesterone facilitates the release. Estrogen excess or progesterone deficiency tends to cause enlargement of the thyroid gland, in association with a hypothyroid state. Estrogen can activate the adrenals to produce cortisol, leading to various harmful effects, including brain aging and bone loss. Progesterone stimulates the adrenals and the ovaries to produce more progesterone, but since progesterone protects against the catabolic effects of cortisol, its effects are the opposite of estrogen’s. Progesterone has antiinflammatory and protective effects, similar to cortisol, but it doesn’t have the harmful effects. In hypothyroidism, there is a tendency to have too much estrogen and cortisol, and too little progesterone.

The blood tests can be useful to demonstrate to physicians what the problem is, but I don’t think they are necessary. There is evidence that having 50 or 100 times as much progesterone as estrogen is desirable, but I don’t advocate “progesterone replacement therapy” in the way it’s often understood. Progesterone can instantly activate the thyroid and the ovaries, so it shouldn’t be necessary to keep using it month after month. If progesterone is used consistently, it can postpone menopause for many years.

Cholesterol is converted to pregnenolone and progesterone by the ovaries, the adrenals, and the brain, if there is enough thyroid hormone and vitamin A, and if there are no interfering factors, such as too much carotene or unsaturated fatty acids. Progesterone deficiency is an indicator that something is wrong, and using a supplement of progesterone without investigating the nature of the problem isn’t a good approach. The normal time to use a progesterone supplement is during the “latter half” of the cycle, the two weeks from ovulation until menstruation. If it is being used to treat epilepsy, cancer, emphysema, migraine or arthritis, or something else so serious that menstrual regularity isn’t a concern, then it can be used at any time. If progesterone is used consistently, it can postpone menopause for many years.”

“Most people are aware of some of the variations of bleeding and clotting that occur commonly. Bleeding gums, nose-bleeds, menstruation and its variations, and the spontaneous bruising (especially on the thighs) that many women have premenstrually, are familiar events that don’t seem to mean much to the medical world. Sometimes nose-bleeds are clearly stress-related, but the usual “explanation” for that association is that high blood pressure simply blows out weak blood vessels. Bleeding gums are sometimes stress related, but high blood pressure is seldom invoked to explain that problem.”

“Menstrual bleeding is a good place to start the investigation of bleeding problems, since its relatively harmless abnormalities are physiologically related to some very serious health problems, such as pregnancy bleeding, abruptio placentae, and eclampsia. Women who die from eclampsia have been found to have massively clotted blood vessels in their brains, but the variety of names for the pregnancy disorders have prevented most people from thinking of pregnancy as a time when there is a high risk of the “thrombohemorrhagic disorders,” a time when the clotting system is under stress. (For about fifteen years after Selye coined the term, only he and some Russians were publishing research on it, and Americans still don’t show much interest in the subject.)

Women with a chronic menstrual problem resulting from progesterone deficiency often continue to bleed each month even when they are pregnant, and these women tend to develop toxemia, and to have a high incidence of pregnancy complications, and to deliver premature, poorly developed babies.

In 1933 James Shute was recommending the use of vitamin E for preventing the clotting problems associated with pregnancy, that often lead to miscarriage. He based his work on animal studies, that led to vitamin E’s being known as the “fertility vitamin.” Later, his sons Wilfred and Evan reported that vitamin E could prevent heart attacks, birth defects, complications of diabetes, phlebitis, hypertension, and some neurological problems.”

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Fish Oils Increase Intestinal Permeability

Also see:
PUFA and Liver Toxicity; Protection by Saturated Fats
Endotoxin: Poisoning from the Inside Out
Ray Peat, PhD on the Benefits of the Raw Carrot
Protection from Endotoxin
Endotoxin-lipoprotein Hypothesis
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Bowel Toxins Accelerate Aging
Liver saving saturated fats

“Besides causing a general slowing of metabolism, aging and toxic PUFA have specific actions on the detoxifying system. The enzymes that help to detoxify PUFA and estrogen and serotonin are inhibited by both PUFA and estrogen. All systems, including blood vessels and the intestine, are made leaky by estrogen and the PUFA and their products.” -Ray Peat, PhD

“In the bowel, the capillary malfunction increases the absorption of endotoxin, which intensifies the systemic energy problem. (Polyunsaturated oils, especially fish oil, damage the bowel capillaries, allowing more endotoxin to be absorbed.)” -Ray Peat, PhD

J Nutr. 2011 Sep;141(9):1635-42. Epub 2011 Jul 20.
Ingestion of (n-3) fatty acids augments basal and platelet activating factor-induced permeability to dextran in the rat mesenteric vascular bed.
Dombrowsky H, Lautenschläger I, Zehethofer N, Lindner B, Schultz H, Uhlig S, Frerichs I, Weiler N.
Loss of intestinal barrier function and subsequent edema formation remains a serious clinical problem leading to hypoperfusion, anastomotic leakage, bacterial translocation, and inflammatory mediator liberation. The inflammatory mediator platelet activating factor (PAF) promotes eicosanoid-mediated edema formation and vasoconstriction. Fish oil-derived (n-3) fatty acids (FA) favor the production of less injurious eicosanoids but may also increase intestinal paracellular permeability. We hypothesized that dietary (n-3) FA would ameliorate PAF-induced vasoconstriction and enhance vascular leakage of dextran tracers. Rats were fed either an (n-3) FA-rich diet (EPA-rich diet; 4.0 g/kg EPA, 2.8 g/kg DHA) or a control diet (CON diet; 0.0 g/kg EPA and DHA) for 3 wk. Subsequently, isolated and perfused small intestines were stimulated with PAF and arterial pressure and the translocation of fluid and macromolecules from the vasculature to lumen and lymphatics were analyzed. In intestines of rats fed the EPA-rich diet, intestinal phospholipids contained up to 470% more EPA and DHA at the expense of arachidonic acid (AA). The PAF-induced increase in arterial pressure was not affected by the EPA-rich diet. However, PAF-induced fluid loss from the vascular perfusate was higher in intestines of rats fed the EPA-rich diet. This was accompanied by a greater basal loss of dextran from the vascular perfusate and a higher PAF-induced transfer of dextran from the vasculature to the lumen (P = 0.058) and lymphatics. Our data suggest that augmented intestinal barrier permeability to fluid and macromolecules is a possible side effect of (n-3) FA-rich diet supplementation.

DHA increases the leakiness of the bowel, allowing more endotoxin to enter the circulation (RoigPerez, et al., 2004). -Ray Peat, PhD

J Lipid Res. 2004 Aug;45(8):1418-28. Epub 2004 Jun 1.
Lipid peroxidation induced by DHA enrichment modifies paracellular permeability in Caco-2 cells: protective role of taurine.
Roig-Pérez S, Guardiola F, Moretó M, Ferrer R.
Dietary enrichment with docosahexaenoic acid (DHA) has numerous beneficial effects on health. However, the intake of high doses of polyunsaturated fatty acids can promote lipid peroxidation and the subsequent propagation of oxygen radicals. The purpose of this study was to evaluate the effect of DHA on lipid peroxidation and tight junction structure and permeability in Caco-2 cell cultures. Moreover, the effects of taurine, a functional ingredient with antioxidant properties, were also tested. Differentiated Caco-2 cell monolayers were maintained in DHA-supplemented conditions with or without added taurine. Incubation with 100 microM DHA increased lipid peroxidation and paracellular permeability, in parallel with a redistribution of the tight junction proteins occludin and ZO-1. Taurine partially prevented all of these effects. The participation of reactive oxygen and nitrogen species in increased paracellular permeability was also examined using various agents that modify the formation of superoxide radical, hydrogen peroxide, nitric oxide, and peroxynitrite. We conclude that hydrogen peroxide and peroxynitrite may be involved in the DHA-induced increase in paracellular permeability and that the protective role of taurine may be in part related to its capacity to counteract the effects of hydrogen peroxide.

Implications:
J Clin Gastroenterol. 2002 Apr;34(4):385-96.
Intestinal permeation and gastrointestinal disease.
DeMeo MT, Mutlu EA, Keshavarzian A, Tobin MC.
The gastrointestinal tract constitutes one of the largest sites of exposure to the outside environment. The function of the gastrointestinal tract in monitoring and sealing the host interior from intruders is called the gut barrier. A variety of specific and nonspecific mechanisms are in operation to establish the host barrier; these include luminal mechanisms and digestive enzymes, the epithelial cells together with tight junctions in between them, and the gut immune system. Disruptions in the gut barrier follow injury from various causes including nonsteroidal anti-inflammatory drugs and oxidant stress, and involve mechanisms such as adenosine triphosphate depletion and damage to epithelial cell cytoskeletons that regulate tight junctions. Ample evidence links gut barrier dysfunction to multiorgan system failure in sepsis and immune dysregulation. Additionally, contribution of gut barrier dysfunction to gastrointestinal disease is an evolving concept and is the focus of this review. An overview of the evidence for the role of gut barrier dysfunction in disorders such as Crohn’s disease, celiac disease, food allergy, acute pancreatitis, non-alcoholic fatty liver disease, and alcoholic liver disease is provided, together with critical insight into the implications of this evidence as a primary disease mechanism.

“Essential” polyunsaturated fat linoleic acid also increase intestinal permeability. Saturated fats had no such effect.
Alcohol Clin Exp Res. 2012 May;36(5):835-46. doi: 10.1111/j.1530-0277.2011.01673.x. Epub 2011 Dec 7.
The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease.
Kirpich IA, Feng W, Wang Y, Liu Y, Barker DF, Barve SS, McClain CJ.
BACKGROUND:
Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD.
METHODS:
C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil) or SF (medium chain triglycerides:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability, and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression, were evaluated.
RESULTS:
After 8 weeks of EtOH feeding, liver injury and steatosis were observed in USF + EtOH group compared with control and SF + EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF + EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared with SF. Importantly, alcohol further suppressed TJ proteins in USF + EtOH, but did not affect intestinal TJ in SF + EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF + EtOH and USF + EtOH groups. CONCLUSIONS: Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that USF (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to USF and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.

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PUFA Kill Thymocytes

“Polyunsaturated fatty acids, derived from foods, have a special role in the immune system, intensifying the effects of stress (cholesterol newsletter, September, 2005) in killing lymphocytes, and blocking the proliferative response of thymic cells (Rotondo, et aI., 1994). They tend to shift immune functions from cellular immunity to humoral (antibody) immunity, and this pattern predisposes to autoimmunity. They are probably directly toxic to the liver (Ritskes-Hoitinga, 1998). DHA increases the leakiness of the bowel, allowing more endotoxin to enter the circulation (RoigPerez, et al., 2004).” -Ray Peat, PhD

Biochim Biophys Acta. 1994 Sep 8;1223(2):185-94.
Inhibition of cytokine-stimulated thymic lymphocyte proliferation by fatty acids: the role of eicosanoids.
Rotondo D, Earl CR, Laing KJ, Kaimakamis D.
The effect of individual fatty acids on the proliferation of thymic lymphocytes in response to interleukin-1 (IL-1) was investigated. Proliferation was estimated by measuring [3H]thymidine incorporation into the acid insoluble fraction of the thymocytes. A concentration-dependent inhibition (in the range 1-100 microM) in the IL-1-stimulated proliferation was observed with the C20 fatty acids dihomo-gamma-linolenic acid (DGLA), arachidonic acid and eicosapentaenoic acid (EPA). A less pronounced concentration-dependent inhibitory response was observed with the C18 fatty acids linoleic acid, alpha-linolenic acid and gamma-linolenic acid. Palmitic acid and oleic did not have any effect on either basal or IL-1-stimulated proliferation at concentrations up to 100 microM. The potencies of each fatty acid for this effect at a concentration of 100 microM were: arachidonic acid > EPA > or = DGLA > linoleic acid. DGLA, arachidonic acid and EPA also attenuated IL-2-stimulated proliferation. The inhibitory action of these fatty acids was not mediated by conversion to prostaglandins or other eicosanoids as the cyclooxygenase inhibitor, ketoprofen and NDGA did not alter their action. Incubation of thymocytes with radiolabelled DGLA and EPA followed by reverse-phase HPLC analysis revealed that DGLA is predominantly converted to a more polar metabolite which is not PGE1 whereas EPA does not appear to be converted to any other detectable metabolite. The data indicate that the inhibitory actions of fatty acids on cell proliferation do not occur as a result of conversion to other metabolites but may be direct effects. The inhibition of cytokine-stimulated lymphocyte proliferation by unsaturated fatty acids would imply that they may attenuate cell-mediated immune reactions.

Thymocytes are much more easily killed by stress than nerve cells, and they are easy to study. The PUFA kill them by increasing their intracellular calcium. The toxicity of DHA is greater than that of EPA, whose toxicity is greater than the alpha-linoleic acid, and linoleic acid was the most potent (Prasad, et al., 2010)…The process by which excitotoxicity kills cells is probably a foreshadowed version of the aging process. -Ray Peat, PhD

J Cell Physiol. 2010 Nov;225(3):829-36.
Role of calcium and ROS in cell death induced by polyunsaturated fatty acids in murine thymocytes.
Prasad A, Bloom MS, Carpenter DO.
We investigated the mechanisms whereby omega-3 and -6 polyunsaturated fatty acids (PUFAs) cause cell death of mouse thymocytes using flow cytometry, focusing on the respective roles of intracellular calcium concentration, [Ca(2+)](i) and reactive oxygen species (ROS). We applied the C-22, 20, and 18 carbon omega-3 (DHA, EPA, ALA) and omega-6 (DTA, ARA, and LNA) fatty acids to isolated thymocytes and monitored cell death using the DNA-binding dye, propidium iodide. When applied at 20 µM concentration, omega-3 fatty acids killed thymocytes over a period of 1 h with a potency of DHA > EPA > ALA. The omega-6 PUFAs were more potent. The C18 omega-6 fatty acid, LNA, was the most potent, followed by DHA and ARA. Cell death was always accompanied by an increase in the levels of [Ca(2+)](i) and ROS. Both increases were in proportion to the potency of the PUFAs in inducing cell death. Removing extracellular calcium did not prevent the elevation in [Ca(2+)](i) nor cell death. However, the intracellular calcium chelator, BAPTA, almost totally reduced both the elevation in [Ca(2+)](i) and cell death, while vitamin E reduced the elevation in ROS and cell death. BAPTA also prevented the elevation in ROS, but vitamin E did not prevent the elevation in [Ca(2+)](i). Thapsigargin, which depletes endoplasmic reticulum calcium, blocked the elevation in [Ca(2+)](i), but CCCP, a mitochondrial calcium uptake inhibitor, did not. These results suggest that the six PUFAs we studied kill thymocytes by causing release of calcium from endoplasmic reticulum, which causes release of ROS from mitochondria which leads to cell death.

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Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging

Also see:
Protect the Mitochondria
Mitochondrial Medicine
PUFA Accumulation & Aging
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Dietary PUFA Reflect in Human Subcutaneous Fat Tissue
Toxicity of Stored PUFA
PUFA, Development, and Allergy Incidence
Estrogen Levels Increase with Age
Fat Tissue and Aging – Increased Estrogen
Unsaturated Fats and Age Pigment
Ray Peat, PhD Quotes on Coconut Oil
Medium Chain Fats from Saturated Fat – Weight Management Friendly
Unsaturated Fats and Longevity
Endotoxin: Poisoning from the Inside Out
Ray Peat, PhD on Endotoxin
PUFA Decrease Cellular Energy Production
Fish Oil Toxicity
Protective “Essential Fatty Acid Deficiency”
Glucocorticoids, Cytochrome Oxidase, and Metabolism
Copper: The Forgotten Essential Nutrient

Quotes Ray Peat, PhD:
“A crucial enzyme in the mitochondrion is cytochrome oxidase, which reacts directly with oxygen, completing (or beginning) the process of chemical respiration. It is this enzyme (which is most sensitive to cyanide) which appears to be a “choke point” for energy production in various situations. Learning how to preserve and promote the activity of this enzyme is an important issue for everything having to do with biological energy…Kunkel and Williams (J. Biol. Chem., 1951) found that the very high respiratory rate of animals fed a diet lacking polyunsaturated fats was caused primarily by a great increase in the activity of cytochrome oxidase, and that adding an “essential fatty acid” strongly inhibited this enzyme’s activity.”

“The absorption and retention of magnesium, sodium, and copper, and the synthesis of proteins, are usually poor in hypothyroidism. Salt craving is common in hypothyroidism, and eating additional sodium tends to raise the body temperature, and by decreasing the produc- tion of aldosterone, it helps to minimize the loss of magnesium, which in turn allows cells to respond better to the thyroid hormone. This is probably why a low sodium diet increases adrenalin production, and why eating enough sodium lowers adrenalin and improves sleep. The lowered adrenalin is also likely to improve intestinal motility.”

“Thyroid hormone is essential for forming carbon dioxide. In the early 1940s, experimental rabbits were fed their standard diet, with the addition of 1% desiccated thyroid gland, which would be equivalent to about 150 grains of Armour thyroid for a person. They became extremely hypermetabolic, and couldn’t eat enough to meet their nutritional needs for growth and tissue maintenance. When they died, all of their tissues weighed much less than those of animals that hadn’t received the toxic dose of thyroid, except for their bones, which were larger than normal. Experiments with the thin skull bones of mice have shown that the active thyroid hormone, T3, increases the formation of bone. To increase cellular respiration and carbon dioxide production, T3 increases the activity of the enzyme cytochrome oxidase, which uses copper as a co-factor. Increased thyroid activity increases the absorption of copper from foods.”

“Just a diet can affect it [cytochrome c oxidase], but stress tends to intensify [the loss of] it. Not getting enough light, anything that stresses your energy production system such as high estrogen or nitric oxide, or low thyroid, or too much darkness will tend to make you lose copper from your respiratory system. And as copper gets lost, iron just tends to fill in for it, binding to some of the same enzymes.”

“Iron and copper are best known for their roles in oxygen transport and utilization… Copper is a component or cofactor for mitochondrial cytochrome oxidases, for dopamine B-oxidase (required for the biosynthesis of norepinephrine and epinephrine, of tyrosinase (involved in the biosynthesis of melanin pigments), and lysyl oxidase (which participates in the formation of collage and elastin).”

“I think the issue is just one of propaganda analysis, because scientifically, no one ever refuted the refutation of essentiality which occurred when the “EFA deficiency syndrome” was cured with vitamin B6. The German demonstration that spontaneous cancer was eliminated on a fat free diet preceded the really awful, incompetent study that supposedly demonstrated the essentiality of polyunsaturated fatty acids, and in the 75 years since the German study a tremendous amount of information has accumulated showing both the toxicity and the non-essentiality of the polyunsaturated fatty acids. But there has been no financial support for publicizing the protective effect of not eating vegetable oils or fish oils. To the contrary, vast amounts of money are being spent in the promotion of the various polyunsaturated fats as foods.”

“The animals that don’t eat them do have increased nutritional needs for vitamins and minerals, because their metabolic rate is so much greater than the PUFA-replete animals whose cardiolipin has degenerated. The recent Stanford study that shows a much greater longevity for old people who have a very high oxygen consumption capacity is consistent with the historical animal studies. PUFA-deprived animals have a very high oxygen consumption, and are resistant to practically all causes of death and disease, including trauma and poisoning.”

“The editorial boards of many of the journals are packed with industry flacks who are apparently willing to publish any junk that helps to sell soy oil, canola, waste fish oil, or algae oils. And researchers have to get grants to stay in business.”

“As early as 1951, it was known (Kunkel and Williams, J. BioI. Chern.) that the polyunsaturated fatty acids strongly inhibit the crucial respiratory enzyme, cytochrome oxidase, and that inhibition of this enzyme has a very important effect on the whole animal suppressing its metabolic rate, reducing the number of calories it can burn. It is now known that polyunsaturated fats interfere with thyroid hornone in just about every conceivable way.”

“The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome oxidase.

“This enzyme is dependent upon the thyroid hormone and is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin. Red light, which passes easily through the tissues, reactivates the enzyme, which slowly loses its function during darkness.”

“Estrogen impairs the mitochondria in multiple ways, including blocking the function of cytochrome oxidase, decreasing the activity of ATP synthase, increasing heme oxygenase which produces carbon monoxide and free iron, damaging mitochondrial DNA, and shifting metabolism from glucose oxidation to fat oxidation, especially by inhibiting pyruvate dehyrogenase complex. These changes including the loss of cytochrome oxidase, are seen in the Alzheimer’s brain. The fact that this kind of energy impairment can be produced by estrogen doesn’t imply that estrogen is the cause, since many other things can cause similar effects–radiation, aluminum, endotoxin, for example.”

“The choice of foods which have less unsaturated fat tends to reinforce the achievements of evolution.”

“The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are antiinflammatory, and some of which act on the “bliss receptor,” or the cannibinoid receptor.

“At birth, the baby’s mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to support the activity of the crucial respiratory enzyme, cytochrome oxidase.”

“The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and this change corresponds to the life-long decline of the person’s metabolic rate.”

“Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by red light, thyroid, and progesterone. It’s a copper enzyme, so it’s likely to be damaged by excess iron. It is most active when it is associated with a mitochondrial lipid, cardiolipin, that contains saturated palmitic acid; the substitution of polyunsaturated fats lowers its activity. Mitochonrial function in general is poisoned by the unsaturated fats, especially arachidonic acid and DHA.”

“The suppressive effects of unsaturated fats on mitochondrial energy production have been widely investigated, since it is that effect that makes animal fattening with PUFA so economical. Rather than interpreting that as a toxic effect, using the innate structure and function of the mitochondrion as a point of reference from which to evaluate dietary components, the consumption of “good” oils is being used as the reference point from which to evaluate the meaning of metabolism (“efficiency is good,” “low oxygen consumption is good”). Building on the idea that the oils are health-promoters which increase metabolic efficiency, the never-viable “rate of aging” theory was resuscitated: The anti-respiratory effect of PUFA is used (illogically) to return to the idea that aging occurs in proportion to the amount of oxygen consumed, because animals which lack the supposedly essential nutrients (“defective animals”) consume oxygen rapidly–burning calories rapidly, they are supposed to be like a candle that won’t last as long if it burns intensely. The old theory is simply resuscitated to explain why the anti-respiratory action of PUFA might be beneficial, justifying further promotion of their use as food and drugs.”

“When mitochondria are functioning fully, either glucose or saturated fats can safely provide energy. Some glucose or saturated fat can be converted to polyunsaturated fats, that can be used as regulators or signals, for example to activate the formation of stem cells. But those PUFA don’t create disruptive cascades of increasing excitation or inflammation or excessive growth, and, from the evidence of animals that are fed fat free diets, or diets lacking omega -3 and omega -6 fatty acids, they aren’t toxic to mitochondria.”

“Increased estrogen exposure, decreased thyroid hormone, an increased ratio of iron to copper, and lack of light, are other factors that impair the cytochrome oxidase enzyme.”

“The crucial mitochondrial respiratory enzyme, cytochrome c oxidase, declines with aging (Paradies, et al., 1997), as the lipid cardiolipin declines, and the enzyme’s activity can be restored to the level of young animals by adding cardiolipin. The composition of cardiolipin changes with aging, “specifically an increase in highly unsaturated fatty acids” (Lee, et al., 2006). Other lipids, such as a phosphatidylcholine containing two myristic acid groups, can support the enzyme’s activity (Hoch, 1992). Even supplementing old animals with hydrogenated peanut oil restores mitochondrial respiration to about 80% of normal (Bronnikov, et al., 2010).”

“Supplementing thyroid hormone increases mitochondrial cardiolipin (Paradies and Ruggiero, 1988). Eliminating the polyunsaturated fats from the diet increases mitochondrial respiration (Rafael, et al., 1984).”

“On a typical diet, tissues progressively accumulate linoleic acid, and this alters the structure of mitochondrial cardiolipin, which governs the response of the mitochondrial enzymes to the thyroid hormone. This process is especially evident in the female liver. In the “autoimmune” diseases, such as lupus, there are typically antibodies to cardiolipin, as if the body were trying to reject its own tissues, which have been altered by the storage of linoleic acid.

The altered mitochondrial function, which is involved in so many symptoms, can become part of a vicious circle, with endotoxin and estrogen having central roles, once the stage has been set by the combination of diet, stress, and toxins.”

J Biol Chem. 1951 Apr;189(2):755-61.
The effects of fat deficiency upon enzyme activity in the rat.
KUNKEL HO, WILLIAMS JN Jr.
The activity of the cytochrome oxidase, however, is markedly increased in fat deficiency…In each case the activity of livers from rats fed the basal diet was 38 per cent greater than from the linoleate-supplemented animals or from the animals receiving corn oil. This is particularly interesting in view of the observation of Burr and Beeber (8) and Wesson and Burr (9) that fat-deficient rats had a markedly increased metabolic rate. The latter authors reported that the basal and assimilatory metabolic rates of fat-deficient animals were 25 per cent greater than the rates of the control animals. Thus the liver cytochrome oxidase activity appears to parallel the met,abolic rate in fat deficiency. This increased cytochrome oxidase activity in liver and perhaps other tissues may account in a large part for the increased metabolic rate.

Summary
A fat deficiency in the rat causes a marked increase in liver cytochrome oxidase activity, a slight increase in choline oxidase activity, and a marked decrease in endogenous respiration. The activity of the succinic oxidase system is not altered by this deficiency condition. Supplementation with 100 mg. of methyl linoleate per rat per day reduced the cytochrome oxidase to the level of that produced by a 5 percent corn oil diet.

FEBS Lett. 1997 Apr 7;406(1-2):136-8.
Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
Cardiolipin is a major mitochondrial membrane lipid and plays a pivotal role in mitochondrial function. We have recently suggested a possible involvement of this phospholipid in the age-linked decline of cytochrome c oxidase activity in rat heart mitochondria [G. Paradies et al. (1993) Arch. Gerontol. Geriatr. 16, 263-272]. The aim of this work was to test our earlier proposal. We have investigated whether addition of exogenous cardiolipin to mitochondria is able to reverse, in situ, the age-linked decrease in the cytochrome oxidase activity. The method of fusion of liposomes with mitochondria developed by Hackenbrock [Hackenbrock and Chazotte (1986) Methods Enzymol. 125, 35-45] was employed in order to enrich the mitochondria cardiolipin content. We demonstrate that the lower cytochrome c oxidase activity in heart mitochondria from aged rats can be fully restored to the level of young control rats by exogenously added cardiolipin. No restoration was obtained with other phospholipids or with peroxidized cardiolipin. Our data support a key role for cardiolipin in the age-linked decline of rat heart mitochondrial cytochrome c oxidase activity.

FEBS Lett. 1999 Jul 9;454(3):207-9.
The effect of aging and acetyl-L-carnitine on the pyruvate transport and oxidation in rat heart mitochondria.
Paradies G, Petrosillo G, Gadaleta MN, Ruggiero FM.
The effect of aging and acute treatment with acetyl-L-carnitine on the pyruvate transport and oxidation in rat heart mitochondria was studied. The activity of the pyruvate carrier as well as the rates of pyruvate-supported respiration were both depressed (around 40%) in heart mitochondria from aged rats, the major decrease occurring during the second year of life. Administration of acetyl-L-carnitine to aged rats almost completely restored the rates of these metabolic functions to the level of young control rats. This effect of acetyl-L-carnitine was not due to changes in the content of pyruvate carrier molecules. The heart mitochondrial content of cardiolipin, a key phospholipid necessary for mitochondrial substrate transport, was markedly reduced (approximately 40%) in aged rats. Treatment of aged rats with acetyl-L-carnitine reversed the age-associated decline in cardiolipin content. As the changes in cardiolipin content were correlated with changes in rates of pyruvate transport and oxidation, it is suggested that acetyl-L-carnitine reverses the age-related decrement in the mitochondrial pyruvate metabolism by restoring the normal cardiolipin content.

Lipids Health Dis. 2006 Jan 23;5:2.
Selective remodeling of cardiolipin fatty acids in the aged rat heart.
Lee HJ, Mayette J, Rapoport SI, Bazinet RP.
BACKGROUND:
The heart is rich in cardiolipin, a phospholipid acylated in four sites, predominately with linoleic acid. Whether or not aging alters the composition of cardiolipin acyl chains is controversial. We therefore measured the fatty acid concentration of cardiolipin in hearts of 4, 12 and 24 month old rats that consumed one diet, adequate in fatty acids for the duration of their life.
RESULTS:
The concentration (nmol/g) of linoleic acid was decreased in 24 month old rats (3965 +/- 617, mean +/- SD) vs 4 month old rats (5525 +/- 656), while the concentrations of arachidonic and docosahexaenoic acid were increased in 24 month old rats (79 +/- 9 vs 178 +/- 27 and 104 +/- 16 vs 307 +/- 68 for arachidonic and docosahexaenoic acids, 4 months vs 24 months, respectively). Similar changes were not observed in ethanolamine glycerophospholipids or plasma unesterified fatty acids, suggesting specificity of these effects to cardiolipin.
CONCLUSION:
These results demonstrate that cardiolipin remodeling occurs with aging, specifically an increase in highly unsaturated fatty acids.

Biochemistry (Mosc). 2010 Dec;75(12):1491-7.
Dietary supplementation of old rats with hydrogenated peanut oil restores activities of mitochondrial respiratory complexes in skeletal muscles.
Bronnikov GE, Kulagina TP, Aripovsky AV.
The effect of dietary supplementation of old rats (26-33 months) with hydrogenated peanut oil on the activity of mitochondrial enzymes in skeletal muscles has been studied. The activities of NADH-coenzyme Q1 oxidoreductase, cytochrome c oxidase, and citrate synthase were determined spectrophotometrically in muscle homogenates. The activities of respiratory complexes I and IV were shown to significantly decrease with the age compared to the activity of the same enzymes in young animals, while the activity of citrate synthase was virtually unchanged. The fatty acid composition of muscle homogenates of old rats differed from that of young animals by a reduced content of myristic, oleic, linoleic, and α-linolenic acids and enhanced content of dihomo-γ-linolenic, arachidonic, and docosahexaenoic acids. Per oral supplementation of the old rats with hydrogenated peanut oil completely restored the activity of complex IV and increased the activity of complex I to 80% of the value observed in muscles of young animals, reducing the content of stearic, dihomo-γ-linolenic, arachidonic, eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids relative to that in the groups of old and young rats. The content of oleic and linoleic acids increased relatively to that in the group of the old rats, as well as young animals. The possible mechanisms of the restoration of the activity of the respiratory enzymes under the administration of hydrogenated peanut oil are discussed.

Biochim Biophys Acta. 1988 Aug 17;935(1):79-86.
Effect of hyperthyroidism on the transport of pyruvate in rat-heart mitochondria.
Paradies G, Ruggiero FM.
A comparative study of the transport of pyruvate in heart mitochondria from normal and triiodothyronine-treated rats has been carried out. It has been found that the rate of carrier-mediated (alpha-cyanocinnamate-sensitive) pyruvate uptake is significantly enhanced in mitochondria from triiodothyronine-treated rats as compared with mitochondria from control rats. The kinetic parameters of the pyruvate uptake indicate that only the Vmax of this process is enhanced whilst there is no change in the Km value. The enhanced rate of pyruvate uptake is not dependent on the increase of the transmembrane delta pH value (both mitochondria from normal and triiodothyronine-treated rats exhibit the same delta pH value) neither does it depend on the increase of the pyruvate carrier molecules (titration of these last with alpha-cyanocinnamate gives the same total number of binding sites). the pyruvate-dependent oxygen uptake is stimulated by 35-40% in mitochondria from hyperthyroid rats when compared with mitochondria from control rats. There is, however, no difference in either the respiratory control ratios or in the ADP/O ratios between these two types of mitochondria. The heart mitochondrial phospholipid composition is altered significantly in hyperthyroid rats; in particular, negatively charged phospholipid such as cardiolipin and phosphatidylserine were found to increase by more than 50%. Minor alterations were found in the pattern of fatty acids with an increase of 20:4/18:2 ratio. It is suggested that the changes in the kinetic parameters of pyruvate transport in mitochondria from hyperthyroid rats involve hormone-mediated changes in the lipid composition of the mitochondrial membranes which in turn modulate the activity of the pyruvate carrier.

J Nutr. 1984 Feb;114(2):255-62.
The effect of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats.
Rafael J, Patzelt J, Schäfer H, Elmadfa I.
Rats were fed a diet poor (0.05%) in essential fatty acids (EFA) with hydrogenated coconut oil as fat component, or a control diet containing 4% of the total energy intake in the form of linoleic acid. Effects of dietary EFA deficiency were investigated during a period of 2-30 weeks. Growth retardation becomes significant after 4 weeks of deficiency and attains about 25% when the deficiency is maintained for longer than 12 weeks. Respiration, body weight and age of EFA-deficient rats and controls are in a nonlinear relationship. Basal respiration in relation to the body weight is significantly increased by EFA deficiency; it is unchanged when related to total animals under the employed experimental conditions. Oxidative phosphorylation in isolated liver mitochondria is unaffected by EFA deficiency, i.e., the increased metabolic rate of EFA-deficient rats, related to the body weight, cannot be explained from impaired functional integrity of the inner mitochondrial membrane. Respiratory chain enzyme activities in mitochondria from heart and skeletal muscle and specific amounts of mitochondria in these tissues are unchanged by EFA deficiency.

Arch Gerontol Geriatr. 1993 May-Jun;16(3):263-72.
Age-dependent decrease in the cytochrome c oxidase activity and changes in phospholipids in rat-heart mitochondria.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
The effect of aging on the kinetic characteristics of cytochrome c oxidase in rat heart mitochondria was investigated. Mitochondria from young and aged rats had equivalent Km values for cytochrome c, while the maximal activity of the oxidase was significantly reduced in mitochondria from aged rats. The cytochrome aa3 content was the same in both these two types of mitochondria. The Arrhenius plot characteristics differ for cytochrome oxidase activity in mitochondria from aged rats as compared with young rats in that the breakpoint of the biphasic plot was shifted to a higher temperature. Cardiolipin content was markedly decreased in mitochondrial membrane from aged rats. No alterations were found in the patterns of the phospholipid fatty acid distribution of mitochondrial membranes from young and aged rats. The results support the conclusion that the reduced mitochondrial cytochrome c oxidase activity in aged animals is due to a specific decrease in the cardiolipin content.

Biochim Biophys Acta. 1995 May 24;1271(1):165-70.
Mitochondrial decay in aging.
Ames BN, Shigenaga MK, Hagen TM.
Several mitochondrial functions decline with age. The contributing factors include, the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

“With aging, cells have less ability to produce energy, and are often more easily stimulated. The accumulation of polyunsaturated fats is one of the factors that reduce the ability of mitochondria to produce energy (Zhang, et al., 2006, 2009; Yazbeck, et al., 1989). Increased estrogen exposure, decreased thyroid hormone, an increased ratio of iron to copper, and lack of light, are other factors that impair the cytochrome oxidase enzyme.” -Ray Peat, PhD

Comp Biochem Physiol A Comp Physiol. 1989;94(2):273-6.
The effects of essential fatty acid deficiency on brown adipose tissue activity in rats maintained at thermal neutrality.
Yazbeck J, Goubern M, Senault C, Chapey MF, Portet R.
1. The consequences of essential fatty acid (EFA) deficiency on the resting metabolism, food efficiency and brown adipose tissue (BAT) thermogenic activity were examined in rats maintained at thermal neutrality (28 C). 2. Weanling male Long-Evans rats were fed a hypolipidic semi-purified diet (control diet: 2% sunflower oil; EFA-deficient diet: 2% hydrogenated coconut oil) for 9 weeks. 3. They were kept at 28 C for the last 5 weeks. Compared to controls, in EFA-deficient rats the growth shortfall reached 21% at killing. 4. As food intake was the same in EFA-deficient and control rats, food efficiency was thus decreased by 40%. 5. Resting metabolism expressed per surface unit was 15% increased. 6. Non-renal water loss was increased by 88%. 7. BAT weight was 28% decreased but total and mitochondrial proteins were not modified. 8. Heat production capacity, tested by GDP binding per BAT was 69% increased in BAT of deficient rats. 9. The stimulation of BAT was established by two other tests: GDP inhibition of mitochondrial O2 consumption and swelling of mitochondria. 10. It is suggested that the observed enhancement of resting metabolism in EFA-deficient rats is, in part, due to an activation of heat production in BAT.

Am J Physiol Cell Physiol. 2006 May;290(5):C1321-33.
Polyunsaturated fatty acids mobilize intracellular Ca2+ in NT2 human teratocarcinoma cells by causing release of Ca2+ from mitochondria.
Zhang BX, Ma X, Zhang W, Yeh CK, Lin A, Luo J, Sprague EA, Swerdlow RH, Katz MS.
In a variety of disorders, overaccumulation of lipid in nonadipose tissues, including the heart, skeletal muscle, kidney, and liver, is associated with deterioration of normal organ function, and is accompanied by excessive plasma and cellular levels of free fatty acids (FA). Increased concentrations of FA may lead to defects in mitochondrial function found in diverse diseases. One of the most important regulators of mitochondrial function is mitochondrial Ca(2+) ([Ca(2+)](m)), which fluctuates in coordination with intracellular Ca(2+) ([Ca(2+)](i)). Polyunsaturated FA (PUFA) have been shown to cause [Ca(2+)](i) mobilization albeit by unknown mechanisms. We have found that PUFA but not monounsaturated or saturated FA cause [Ca(2+)](i) mobilization in NT2 human teratocarcinoma cells. Unlike the [Ca(2+)](i) response to the muscarinic G protein-coupled receptor agonist carbachol, PUFA-mediated [Ca(2+)](i) mobilization in NT2 cells is independent of phospholipase C and inositol-1,4,5-trisphospate (IP(3)) receptor activation, as well as IP(3)-sensitive internal Ca(2+) stores. Furthermore, PUFA-mediated [Ca(2+)](i) mobilization is inhibited by the mitochondria uncoupler carboxyl cyanide m-chlorophenylhydrozone. Direct measurements of [Ca(2+)](m) with X-rhod-1 and (45)Ca(2+) indicate that PUFA induce Ca(2+) efflux from mitochondria. Further studies show that ruthenium red, an inhibitor of the mitochondrial Ca(2+) uniporter, blocks PUFA-induced Ca(2+) efflux from mitochondria, whereas inhibitors of the mitochondrial permeability transition pore cyclosporin A and bongkrekic acid have no effect. Thus PUFA-gated Ca(2+) release from mitochondria, possibly via the Ca(2+) uniporter, appears to be the underlying mechanism for PUFA-induced [Ca(2+)](i) mobilization in NT2 cells.

PLoS ONE 4(6): e6048. doi:10.1371/journal.pone.0006048
Linoleic Acid-Induced Mitochondrial Ca2+ Efflux Causes Peroxynitrite Generation and Protein Nitrotyrosylation
Hong-Mei Zhang1, Howard Dang2, Chih-Ko Yeh3,4, Bin-Xian Zhang1,4*
It is well known that excessive non-esterified fatty acids in diabetes contribute to the pathogenesis of renal complications although the mechanism remains elusive. Enhanced oxidative stress has been hypothesized as a unified factor contributing to diabetic complications and increased protein nitrotyrosylation has been reported in the kidneys of diabetic patients. In the current manuscript we described that linoleic acid (LA) caused mitochondrial Ca2+ efflux and peroxynitrite production, along with increased nitrotyrosine levels of cellular proteins in primary human mesangial cells. The peroxynitrite production by LA was found to depend on mitochondrial Ca2+ efflux. Downregulation of hsp90β1, which has been previously shown to be essential for polyunsaturated fatty acid-induced mitochondrial Ca2+ efflux, significantly diminished LA-responsive mitochondrial Ca2+ efflux and the coupled peroxynitrite generation, implicating a critical role of hsp90β1 in the LA responses. Our results further demonstrated that mitochondrial complexes I and III were directly involved in the LA-induced peroxynitrite generation. Using the well established type 2 diabetic animal model db/db mice, we observed a dramatically enhanced LA responsive mitochondrial Ca2+ efflux and protein nitrotyrosylation in the kidney. Our study thus demonstrates a cause-effect relationship between LA and peroxynitrite or protein nitrotyrosylation and provides a novel mechanism for lipid-induced nephropathy in diabetes.

Endocrine. 2011 Apr;39(2):128-38. Epub 2010 Dec 15.
Long-term exposure of INS-1 rat insulinoma cells to linoleic acid and glucose in vitro affects cell viability and function through mitochondrial-mediated pathways.
Tuo Y, Wang D, Li S, Chen C.
Obesity with excessive levels of circulating free fatty acids (FFAs) is tightly linked to the incidence of type 2 diabetes. Insulin resistance of peripheral tissues and pancreatic β-cell dysfunction are two major pathological changes in diabetes and both are facilitated by excessive levels of FFAs and/or glucose. To gain insight into the mitochondrial-mediated mechanisms by which long-term exposure of INS-1 cells to excess FFAs causes β-cell dysfunction, the effects of the unsaturated FFA linoleic acid (C 18:2, n-6) on rat insulinoma INS-1 β cells was investigated. INS-1 cells were incubated with 0, 50, 250 or 500 μM linoleic acid/0.5% (w/v) BSA for 48 h under culture conditions of normal (11.1 mM) or high (25 mM) glucose in serum-free RPMI-1640 medium. Cell viability, apoptosis, glucose-stimulated insulin secretion, Bcl-2, and Bax gene expression levels, mitochondrial membrane potential and cytochrome c release were examined. Linoleic acid 500 μM significantly suppressed cell viability and induced apoptosis when administered in 11.1 and 25 mM glucose culture medium. Compared with control, linoleic acid 500 μM significantly increased Bax expression in 25 mM glucose culture medium but not in 11.1 mM glucose culture medium. Linoleic acid also dose-dependently reduced mitochondrial membrane potential (ΔΨm) and significantly promoted cytochrome c release from mitochondria in both 11.1 mM glucose and 25 mM glucose culture medium, further reducing glucose-stimulated insulin secretion, which is dependent on normal mitochondrial function. With the increase in glucose levels in culture medium, INS-1 β-cell insulin secretion function was deteriorated further. The results of this study indicate that chronic exposure to linoleic acid-induced β-cell dysfunction and apoptosis, which involved a mitochondrial-mediated signal pathway, and increased glucose levels enhanced linoleic acid-induced β-cell dysfunction.

FEBS Lett. 1996 Nov 18;397(2-3):260-2.
Stimulation of carnitine acylcarnitine translocase activity in heart mitochondria from hyperthyroid rats.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
The effect of hyperthyroidism on fatty acid oxidation and on carnitine-acylcarnitine translocase activity in rat heart mitochondria has been studied. The rates of palmitoylcarnitine supported respiration as well as the carnitine-palmitoylcarnitine exchange reaction were both stimulated (approx. 36%) in heart mitochondria from hyperthyroid rats. Kinetic analysis of the carnitine-carnitine exchange reaction showed that thyroid hormone affects the Vmax of this process, while having no effect on the Km values. The level of cardiolipin was significantly higher (approx. 40%) in heart mitoplasts from hyperthyroid rats than from the control rats. It can be concluded that thyroid hormones produce a stimulation of heart mitochondrial carnitine translocase activity and that the basis of this effect is likely an increase in the cardiolipin content.

FEBS Lett. 1998 Mar 13;424(3):155-8.
Peroxidative damage to cardiac mitochondria: cytochrome oxidase and cardiolipin alterations.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
Rat heart mitochondrial membranes exposed to the free radicals generating system tert-butylhydroperoxide/Cu2+ undergo lipid peroxidation as evidenced by the accumulation of thyobarbituric acid reactive substances. Mitochondrial lipid peroxidation resulted in a marked loss of both cytochrome c oxidase activity and cardiolipin content. The alterations in the properties of cytochrome c oxidase were confined to a decrease in the maximal activity (Vmax) with no change in the affinity (Km) with respect to the substrate cytochrome c. Various lipid soluble antioxidants could prevent the lipid peroxidation reaction and the associated loss of cytochrome c oxidase activity. External added cardiolipin but no other phospholipids, nor peroxidized cardiolipin was able to prevent the loss of cytochrome oxidase activity induced by lipid peroxidation. These results establish a close correlation between oxidative damage to cardiolipin and alterations in the cytochrome oxidase activity and may prove useful in probing molecular mechanism of free radicals induced peroxidative damage of mitochondria which has been proposed to contribute to aging and to chronic degenerative diseases.

Biochim Biophys Acta. 1994 Jan 11;1225(2):165-70.
Enhanced cytochrome oxidase activity and modification of lipids in heart mitochondria from hyperthyroid rats.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
In order to further investigate the mechanism regulating the control of mitochondrial respiration by thyroid hormones, the effect of the hyperthyroidism on the kinetic characteristics of cytochrome c oxidase in rat heart mitochondria was studied. Mitochondrial preparations from both control and hyperthyroid rats had equivalent Km values for cytochrome c, while the maximal activity of cytochrome oxidase was significantly increased (by around 30%) in mitochondrial preparation from hyperthyroid rats. This enhanced activity of cytochrome oxidase was associated to a parallel increase in mitochondrial State 3 respiration. The hormone treatment resulted in a decrease in the flux control coefficient of the oxidase. The enhanced activity of cytochrome oxidase in hyperthyroid rats does not appear to be dependent on an increase in the mass of this enzyme complex in that the heme aa3 content was equivalent in both hyperthyroid and control preparations. The Arrhenius plot characteristics differ for cytochrome oxidase activity in mitochondria from hyperthyroid rats as compared with control rats in that the breakpoint of the biphasic plot is shifted to a lower temperature. Cardiolipin content was significantly increased in mitochondrial preparations from hyperthyroid rats, while there were no significant alterations in the fatty acid composition of cardiolipin of control and hyperthyroid preparations. The results support the conclusion that the enhanced cytochrome oxidase activity in heart mitochondrial preparations from hyperthyroid rats is due to a specific increase in the content of cardiolipin.

Biochim Biophys Acta. 1997 Dec 31;1362(2-3):193-200.
Alterations in carnitine-acylcarnitine translocase activity and in phospholipid composition in heart mitochondria from hypothyroid rats.
Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
Changes in mitochondrial fatty acid metabolism may underlie the decline in cardiac function in the hypothyroid animals. The effect of hypothyroidism on fatty acid oxidation, carnitine-acylcarnitine translocase activity and lipid composition in rat heart mitochondria has been examined. Rates of mitochondrial fatty acid oxidation as well as carnitine-carnitine and carnitine-palmitoylcarnitine exchange reactions were all depressed in heart mitochondria isolated from hypothyroid rats. Kinetic analysis of the carnitine-carnitine exchange reaction showed that the hypothyroid state affects the Vmax of this process, while having no effect on the K(m) value. Heart mitochondrial inner membrane lipid composition was significantly altered in hypothyroid rats. Cardiolipin, particularly, was found to decrease (by around 36%). Alterations in fatty acid pattern of mitochondrial inner membrane preparations from hypothyroid rats were also found. The effects of the hypothyroid state on fatty acids oxidation, carnitine translocase activity and phospholipid composition were completely reversed by following treatment of hypothyroid rats with thyroid hormone. A lower cardiolipin content in the mitochondrial inner membrane offers a plausible mechanism to explain the decline in the translocase activity in hypothyroidism.

Arch Biochem Biophys. 1993 Nov 15;307(1):91-5.
Decreased cytochrome oxidase activity and changes in phospholipids in heart mitochondria from hypothyroid rats.
Paradies G, Ruggiero FM, Dinoi P, Petrosillo G, Quagliariello E.
The effect of hypothyroidism on kinetic characteristics of cytochrome oxidase in rat heart mitochondria was studied. Mitochondrial preparations from control and hypothyroid rats had equivalent Km values for cytochrome c, while the maximal activity of the oxidase was significantly decreased (more than 30%) in mitochondrial preparations from hypothyroid rats. This decrease is associated to a parallel decrease in state 3 respiration. The cytochrome aa3 content was slightly decreased (by around 15%) in mitochondria from hypothyroid rats. The Arrhenius plot characteristics differ for cytochrome oxidase activity in mitochondria from hypothyroid rats as compared with control rats in that the breakpoint of the biphasic plot is shifted to a higher temperature. Cardiolipin content was markedly decreased in the mitochondrial membrane from hypothyroid rats. No alterations were found in the pattern of cardiolipin fatty acid distribution of mitochondrial membrane from control and hypothyroid rats. The effects of the hypothyroid state on the activity of cytochrome oxidase, on cytochrome aa3 levels, and on cardiolipin contents were completely reversed by following the treatment of hypothyroid rats with thyroid hormone. The results support the conclusion that the depressed mitochondrial cytochrome oxidase activity in the hypothyroid state is due, at least in part, to a decrease in the cardiolipin content of the mitochondrial inner membrane.

Biochim Biophys Acta. 1997 Mar 28;1319(1):5-8.
Cardiolipin-dependent decrease of cytochrome c oxidase activity in heart mitochondria from hypothyroid rats.
Paradies G, Petrosillo G, Ruggiero FM.
Cardiolipin plays an important role in mitochondrial membrane structure and function. We have recently reported a decrease in the cytochrome c oxidase activity in heart mitochondria from hypothyroid rats (G. Paradies et al. (1993) Arch. Biochem Biophys. 307, 91-95). A possible involvement of cardiolipin in such a decrease has been proposed. The aim of this work was to test our earlier proposal. We have investigated whether addition of exogenous cardiolipin to hypothyroid mitochondria is able to reverse, in situ, their decreased cytochrome oxidase activity. The method of fusion of liposomes with mitochondria developed by Hackenbrock (Hackenbrock and Chazotte (1986) Methods Enzymol. 125, 35-45) was employed in order to enrich the mitochondrial cardiolipin content. We demonstrate that the decreased activity of this enzyme complex in heart mitochondria from hypothyroid rats can be completely restored to the level of control rats by exogenously added cardiolipin but not by other phospholipids. These data provide strong evidence for the involvement of cardiolipin in the thyroid hormone induced changes of mitochondrial cytochrome oxidase activity.

Mitochondrion. 2001 Aug;1(2):151-9.
Reactive oxygen species generated by the mitochondrial respiratory chain affect the complex III activity via cardiolipin peroxidation in beef-heart submitochondrial particles.
Paradies G, Petrosillo G, Pistolese M, Ruggiero FM.
The aim of this study was to investigate the effect of reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, on the activity of complex III and on the cardiolipin content in bovine-heart submitochondrial particles (SMP). ROS were produced by treatment of nicotinamide adenine dinucleotide (NADH) respiring SMP with rotenone. This treatment resulted in a production of superoxide anion, detected by the epinephrine method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to mitochondrial-mediated ROS generation resulted in a marked loss of complex III activity and in a parallel loss of mitochondrial cardiolipin content. Both these effects were completely abolished by SOD + catalase. Exogenous added cardiolipin was able to almost completely prevent the ROS-mediated loss of complex III activity. No effect was obtained with other major phospholipid components of the mitochondrial membrane such as phosphatidylcholine and phosphatidylethanolamine, or with peroxidized cardiolipin. The results demonstrate that mitochondrial-mediated ROS generation affects the activity of complex III via peroxidation of cardiolipin, which is required for the functioning of this multisubunit enzyme complex. These results may prove useful in probing molecular mechanisms of ROS-induced peroxidative damage to mitochondria, which have been proposed to contribute to those physiopathological conditions characterized by an increase in the basal production of ROS such as aging, ischemia/reperfusion and chronic degenerative diseases.

Free Radic Biol Med. 1999 Jul;27(1-2):42-50.
Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion.
Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Serena D, Ruggiero FM.
Ischemia-reperfusion injury to cardiac myocytes involves membrane damage mediated by oxygen free radicals. Lipid peroxidation is considered a major mechanism of oxygen free radical toxicity in reperfused heart. Mitochondrial respiration is an important source of these reactive oxygen species and hence a potential contributor to reperfusion injury. We have examined the effects of ischemia (30 min) and ischemia followed by reperfusion (15 min) of rat hearts, on the kinetic parameters of cytochrome c oxidase, on the respiratory activities and on the phospholipid composition in isolated mitochondria. Mitochondrial content of malonyldialdheyde (MDA), an index of lipid peroxidation, was also measured. Reperfusion was accompanied by a significant increase in MDA production. Mitochondrial preparations from control, ischemic and reperfused rat heart had equivalent Km values for cytochrome c, although the maximal activity of the oxidase was 25 and 51% less in ischemic and reperfused mitochondria than that of controls. These changes in the cytochrome c oxidase activity were associated to parallel changes in state 3 mitochondrial respiration. The cytochrome aa3 content was practically the same in these three types of mitochondria. Alterations were found in the mitochondrial content of the major phospholipid classes, the most pronounced change occurring in the cardiolipin, the level that decreased by 28 and by 50% as function of ischemia and reperfusion, respectively. The lower cytochrome c oxidase activity in mitochondria from reperfused rat hearts could be almost completely restored to the level of control hearts by exogenously added cardiolipin, but not by other phospholipids nor by peroxidized cardiolipin. It is proposed that the reperfusion-induced decline in the mitochondrial cytochrome c oxidase activity can be ascribed, at least in part, to a loss of cardiolipin content, due to peroxidative attack of its unsaturated fatty acids by oxygen free radicals. These findings may provide an explanation for some of the factors that lead to myocardial reperfusion injury.

Gene. 2002 Mar 6;286(1):135-41.
Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage.
Paradies G, Petrosillo G, Pistolese M, Ruggiero FM.
The aim of this study was to investigate the influence of reactive oxygen species (ROS) on the activity of complex I and on the cardiolipin content in bovine heart submitochondrial particles (SMP). ROS were generated through the use of xanthine/xanthine oxidase (X/XO) system. Treatment of SMP with X/XO resulted in a large production of superoxide anion, detected by acetylated cytochrome c method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to ROS generation resulted in a marked loss of complex I activity and to parallel loss of mitochondrial cardiolipin content. Both these effects were completely abolished by SOD+catalase. Exogenous added cardiolipin was able to almost completely restore the ROS-induced loss of complex I activity. No restoration was obtained with other major phospholipid components of the mitochondrial membrane such as phosphatidylcholine and phosphatidylethanolamine, nor with peroxidized cardiolipin. These results demonstrate that ROS affect the mitochondrial complex I activity via oxidative damage of cardiolipin which is required for the functioning of this multisubunit enzyme complex. These results may prove useful in probing molecular mechanisms of ROS-induced peroxidative damage to mitochondria, which have been proposed to contribute to those pathophysiological conditions characterized by an increase in the basal production of reactive oxygen species such as aging, ischemia/reperfusion and chronic degenerative diseases.

FEBS Lett. 2000 Jan 28;466(2-3):323-6.
The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles.
Paradies G, Petrosillo G, Pistolese M, Ruggiero FM.
The effect of reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, on the activity of cytochrome c oxidase and on the cardiolipin content in bovine heart submitochondrial particles (SMP) was studied. ROS were produced by treatment of succinate-respiring SMP with antimycin A. This treatment resulted in a large production of superoxide anion, measured by epinephrine method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to mitochondrial mediated ROS generation, led to a marked loss of cytochrome c oxidase activity and to a parallel loss of cardiolipin content. Both these effects were completely abolished by SOD+catalase. Added cardiolipin was able to almost completely restore the ROS-induced loss of cytochrome c oxidase activity. No restoration was obtained with peroxidized cardiolipin. These results demonstrate that mitochondrial mediated ROS generation affects the activity of cytochrome c oxidase via peroxidation of cardiolipin which is needed for the optimal functioning of this enzyme complex. These results may prove useful in probing molecular mechanism of ROS-induced peroxidative damage to mitochondria which have been proposed to contribute to aging, ischemia/reperfusion and chronic degenerative diseases.

Circ Res. 2004 Jan 9;94(1):53-9. Epub 2003 Dec 1.
Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin.
Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM.
Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration is an important source of ROS production and hence a potential contributor to cardiac reperfusion injury. In this study, we have examined the effect of ischemia and ischemia followed by reperfusion of rat hearts on various parameters related to mitochondrial function, such as complex I activity, oxygen consumption, ROS production, and cardiolipin content. The activity of complex I was reduced by 25% and 48% in mitochondria isolated from ischemic and reperfused rat heart, respectively, compared with the controls. These changes in complex I activity were associated with parallel changes in state 3 respiration. The capacity of mitochondria to produce H2O2 increased on reperfusion. The mitochondrial content of cardiolipin, which is required for optimal activity of complex I, decreased by 28% and 50% as function of ischemia and reperfusion, respectively. The lower complex I activity in mitochondria from reperfused rat heart could be completely restored to the level of normal heart by exogenous added cardiolipin. This effect of cardiolipin could not be replaced by other phospholipids nor by peroxidized cardiolipin. It is proposed that the defect in complex I activity in ischemic/reperfused rat heart could be ascribed to a ROS-induced cardiolipin damage. These findings may provide an explanation for some of the factors responsible for myocardial reperfusion injury.

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PUFA Inhibit Glucuronidation

Also see:
PUFA Increases Estrogen
PUFA and Liver Toxicity; Protection by Saturated Fats
Protective “Essential Fatty Acid Deficiency”

Quotes by Ray Peat, PhD:
“One of the essential protective functions that decline with aging is the liver’s ability to detoxify chemicals, by combining them with glucuronic acid, making them water soluble so that they can be excreted in the urine. The liver (and also the intestines and stomach) efficiently process DHA by glucuronidation.”

“Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can be modulated.”

“Besides causing a general slowing of metabolism, aging and toxic PUFA have specific actions on the detoxifying system. The enzymes that help to detoxify PUFA and estrogen and serotonin are inhibited by both PUFA and estrogen. All systems, including blood vessels and the intestine, are made leaky by estrogen and the PUFA and their products.”

“But when the endogenous omega-9 fatty acids have been thoroughly displaced by dietary omega-6 and omega -3 fatty acids, the systemic release of fatty acids becomes an amplifier of the stress state initiated by injury or other stress. The liver, for example, decreases its detoxification of estrogen in the presence of polyunsaturated fatty acids.”

Drug Metab Dispos. 2002 May;30(5):531-3.
Glucuronidation of the dietary fatty acids, phytanic acid and docosahexaenoic acid, by human UDP-glucuronosyltransferases.
Little JM, Williams L, Xu J, Radominska-Pandya A.
Linoleic acid has recently been shown to be glucuronidated in vitro by human liver and intestinal microsomes and recombinant UGT2B7. In the present study, the dietary fatty acids (FA), phytanic acid (PA), and docosahexaenoic acid (DHA) have been used as substrates for human UDP-glucuronosyltransferases (UGTs). Both compounds were effectively glucuronidated by human liver microsomes (HLM; 1.25 +/- 0.36 and 1.12 +/- 0.32 nmol/mg x min for PA and DHA, respectively) and UGT2B7 (0.71 and 0.53 nmol/mg x min). Kinetic analysis produced relatively low K(m) values for PA with both HLM and UGT2B7 (149 and 108 microM, respectively). The K(m) for DHA glucuronidation by HLM (460 microM) was considerably higher than that for UGT2B7 (168 microM), suggesting the involvement in microsomes of other UGT isoforms in addition to UGT2B7. Glucuronidation of PA and DHA by gastrointestinal microsomes from 16 human subjects was determined. In general, both PA and DHA were glucuronidated by gastric and intestinal microsomes, and activity toward both substrates was lowest in the stomach, increased in the small intestine, and lower in the colon. However, there were large interindividual variations in UGT activity toward both substrates in all segments of the intestine, as has been seen with other substrates. Thus, PA and DHA are effective in vitro substrates for human liver, gastric and intestinal microsomes, and glucuronidation may play a role in modulating the availability of these FA as ligands for nuclear receptors.

Glucuronidation is inhibited by PUFA increasing accumulation of these fats with aging.

Biochem Pharmacol. 2004 Jan 1;67(1):191-9.
Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7.
Tsoutsikos P, Miners JO, Stapleton A, Thomas A, Sallustio BC, Knights KM.
Renal ischaemia is associated with accumulation of fatty acids (FA) and mobilisation of arachidonic acid (AA). Given the capacity of UDP-glucuronosyltransferase (UGT) isoforms to metabolise both drugs and FA, we hypothesised that FA would inhibit renal drug glucuronidation. The effect of FA (C2:0-C20:5) on 4-methylumbelliferone (4-MU) glucuronidation was investigated using human kidney cortical microsomes (HKCM) and recombinant UGT1A9 and UGT2B7 as the enzyme sources. 4-MU glucuronidation exhibited Michaelis-Menten kinetics with HKCM (apparent K(m) (K(m)(app)) 20.3 microM), weak substrate inhibition with UGT1A9 (K(m)(app) 10.2 microM, K(si) 289.6 microM), and sigmoid kinetics with UGT2B7 (S(50)(app)440.6 microM) Similarly, biphasic UDP-glucuronic acid (UDPGA) kinetics were observed with HKCM (S(50) 354.3 microM) and UGT1A9 (S(50) 88.2 microM). In contrast, the Michaelis-Menten kinetics for UDPGA observed with UGT2B7 (K(m)(app) 493.2 microM) suggested that kinetic interactions with UGTs were specific to the xenobiotic substrate and the co-substrate (UDPGA). FA (C16:1-C20:5) significantly inhibited (25-93%) HKCM, UGT1A9 or UGT2B7 catalysed 4-MU glucuronidation. Although linoleic acid (LA) and AA were both competitive inhibitors of 4-MU glucuronidation by HKCM (K(i)(app) 6.34 and 0.15 microM, respectively), only LA was a competitive inhibitor of UGT1A9 (K(i)(app) 4.06 microM). In contrast, inhibition of UGT1A9 by AA exhibited atypical kinetics. These data indicate that LA and AA are potent inhibitors of 4-MU glucuronidation catalysed by human kidney UGTs and recombinant UGT1A9 and UGT2B7. It is conceivable therefore that during periods of renal ischaemia FA may impair renal drug glucuronidation thus compromising the protective capacity of the kidney against drug-induced nephrotoxicity.

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High PUFA to Saturated Fat Ratio Increase All-Cause Mortality

Exp Gerontol. 2005 Apr;40(4):335-43.
Unsaturated fatty acids intake and all-causes mortality: a 8.5-year follow-up of the Italian Longitudinal Study on Aging.
Solfrizzi V, D’Introno A, Colacicco AM, Capurso C, Palasciano R, Capurso S, Torres F, Capurso A, Panza F.
Recent evidence suggested a protective role of dietary monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) intakes against several chronic diseases and, therefore, an increased human longevity. After a median follow-up of 8.5 years, we investigated the possible role of MUFA, PUFA, and other selected food groups in protecting against all-causes mortality in a population-based, prospective study, conducted in one of the eight centers of the Italian Longitudinal Study on Aging (ILSA), Casamassima, Bari, Italy. Out of 704 elderly subjects (65-84 years), 278 nondemented persons agreed to participate at the first survey (1992-1993). During the follow-up, there were 91 deaths. A semi-quantitative food frequency questionnaire evaluating macronutrient daily intakes were performed at the first survey. Higher MUFA intake was associated with an increase of survival (hazard ratio 0.81, 95% CI 0.66-0.99), a higher unsaturated fatty acids (UFA) to SFA ratio (hazard ratio 1.20, 95% CI 0.99-1.45) increased total mortality only marginally, while no effect about other selected food groups were found. In conclusion, in this prospective study on older nondemented subjects with a typical Mediterranean diet, a higher MUFA intake increased survival, while a higher UFA/SFA ratio increased total mortality, but only marginally.

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Omega -3 Fats Lower Endurance

The least stable n-3 fats which accumulate with age and gradually reduce energy production also have their short term effects on endurance. Endurance was much lower in rats fed a high n-3 fat diet, and the effect persisted even after 6 weeks on a standard diet (Ayre and Hulbert, 1997). -Ray Peat, PhD

Lipids. 1997 Dec;32(12):1265-70.
Dietary fatty acid profile affects endurance in rats.
Ayre KJ, Hulbert AJ.
Typically athletes are advised to increase their consumption of carbohydrates for energy and, along with the general population, to reduce consumption of saturated fats. It is now recognized that fats are not identical in their influence on metabolism, and we argue that the composition of the polyunsaturated fat component should not be ignored. The aim of this study was to manipulate the dietary fatty acid profile in a high-carbohydrate diet in order to investigate the effect of dietary polyunsaturates on submaximal endurance performance in rats. Rats were fed one of three isoenergetic diets containing 22 energy percentage (E%) fat for 9 wk. The diets comprised an essential fatty acid-deficient diet (containing mainly saturated fatty acids); a diet high in n-6 fatty acids, High n-6; and a diet enriched with n-3 fatty acids, High n-3. Submaximal endurance in rats fed the High n-3 diet was 44% less than in rats fed the High n-6 diet (P < 0.02). All rats were then fed a standard commercial laboratory diet for a 6-wk recovery period, and their performances were reevaluated. Although endurance in all groups was lower then at 9 wk, it was again significantly 50% lower in the High n-3 group than the High n-6 group (P < 0.005). Although n-3 fats are considered beneficial for cardiovascular health, they appear to reduce endurance times, and their side effects need to be further investigated.

Analogous, but less extreme effects are seen even in salmon, which showed increased oxidative stress on a high n-3 diet (DHA and EPA), and lower mitochondrial cytochrome oxidase activity (Kjaer, et al., 2008). -Ray Peat, PhD

Lipids. 2008 Sep;43(9):813-27. Epub 2008 Jul 10.
Dietary n-3 HUFA affects mitochondrial fatty acid beta-oxidation capacity and susceptibility to oxidative stress in Atlantic salmon.
Kjaer MA, Todorcević M, Torstensen BE, Vegusdal A, Ruyter B.
Atlantic salmon (Salmo salar) (90 g) were fed four different diets for 21 weeks (final weight 344 g). The levels of n-3 highly unsaturated fatty acids (HUFA) ranged from 11% of the total fatty acids (FA) in the low n-3 diet to 21% in the intermediate n-3 diet, to 55 and 58% in the high n-3 diets. The high n-3 diets were enriched with either docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA). Increasing dietary levels of n-3 HUFA led to increasing percentages (from 31 to 52%) of these FA in liver lipids. The group fed the highest level of DHA had higher expressions of peroxisome proliferator-activated receptor (PPAR) beta and the FA beta-oxidation genes acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase (CPT)-II, compared to the low n-3 groups. The high n-3 groups had reduced activity of mitochondrial cytochrome c oxidase and beta-oxidation capacity, together with increased activities of superoxide dismutase (SOD) and caspase-3 activities. In the group fed the highest level of n-3 HUFA, decreased percentages of major phospholipids (PL) in the mitochondrial and microsomal membranes of the liver were also apparent. The percentage of mitochondrial cardiolipin (Ptd(2)Gro) was 3.1 in the highest n-3 group compared to 6.6 in the intermediate group. These data clearly show an increased incidence of oxidative stress in the liver of fish fed the high n-3 diets.

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Saturated and Monousaturated Fatty Acids Selectively Retained by Fat Cells

Also see:
Toxicity of Stored PUFA
PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
PUFA Accumulation & Aging
Unsaturated Fats and Longevity
Arachidonic Acid’s Role in Stress and Shock
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide
Benefits of Aspirin
Ray Peat, PhD on Low Blood Sugar & Stress Reaction
Low Blood Sugar Basics
Medium Chain Fats, Ketones, and Brain Function
Medium Chain Fats from Saturated Fat – Weight Management Friendly

Quotes by Ray Peat, PhD:
“Saturated and monounsaturated fatty acids are selectively retained by fat cells (Speake, et al., 1997).”

“When we don’t eat for many hours, our glycogen stores decrease, and adrenaline secretion is increased, liberating more glucose as long as glycogen is available, but also liberating fatty acids from the fatty tissues. When the diet has chronically contained more polyunsaturated fats than can be oxidized immediately or detoxified by the liver, the fat stores will contain a disproportionate amount of them, since fat cells preferentially oxidize saturated fats for their own energy, and the greater water solubility of the PUFA causes them to be preferentially released into the bloodstream during stress.

In good health, especially in children, the stress hormones are produced only in the amount needed, because of negative feedback from the free saturated fatty acids, which inhibit the production of adrenalin and adrenal steroids, and eating protein and carbohydrate will quickly end the stress. But when the fat stores contain mainly PUFA, the free fatty acids in the serum will be mostly linoleic acid and arachidonic acid, and smaller amounts of other unsaturated fatty acids. These PUFA stimulate the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the stress reaction is self limiting, but under the influence of PUFA, the stress response becomes self-amplifying.

When stress is very intense, as in trauma or sepsis, the reaction of liberating fatty acids can become dangerously counter-productive, producing the state of shock. In shock, the liberation of free fatty acids interferes with the use of glucose for energy and causes cells to take up water and calcium (depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al, 2004; van der Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often leading to death.”

“My argument here will be that some of our adaptive, protective regulatory processes are overridden by the excessive supply of unsaturated fats–supported by a few other toxins–in our diet, acting as a false-signal system, and that cholesterol, pregnenolone, and progesterone which are our main long-range defenses, are overcome by the effects of the unsaturated fats, and that the resulting cascade of ineffective and defective reactions (including various estrogen-stimulated processes) leads to lower and lower energy production, reduced function, and death. At certain times, especially childhood and old age, iron (which also has important regulatory roles) accumulates to the point that its signal functions may be inappropriate.”

Biochim Biophys Acta. 1997 Apr 21;1345(3):317-26.
The preferential mobilisation of C20 and C22 polyunsaturated fatty acids from the adipose tissue of the chick embryo: potential implications regarding the provision of essential fatty acids for neural development.
Speake BK, Cerolini S, Maldjian A, Noble RC.
The aim of this study was to determine the relative mobilisation of the different fatty acyl components of the triacylglycerol (TAG) of the chick embryo’s adipose tissue in the light of the specific requirements of the developing neural tissues of the embryo for C20-22 polyunsaturated fatty acids. Pieces of adipose tissue, obtained from embryos at various developmental stages, were incubated in vitro in Dulbecco’s Medium containing serum albumen. The fatty acid compositions of the initial tissue TAG and of the free fatty acid (FFA) mobilised from the tissue during 1 h of incubation were determined and compared. The composition of the FFA released into the medium under conditions of basal (i.e., unstimulated) lipolysis was markedly different in several respects from that of the TAG from which it originated. The polyunsaturated fatty acids, 20:4n-6, 20:5n-3, 22:5n-3 and 22:6n-3, were consistently found to be preferentially released into the medium, whereas the major fatty acyl constituents of the tissue, 16:0 and 18:1n-9, were selectively retained in the TAG. For example, at day 18 of development, the proportions (% w/w of fatty acids) of 20:5n-3 and 22:6n-3 released into the incubation medium were respectively 6.5 and 7.5 times higher than in the original tissue TAG. Glucagon stimulated the overall rate of mobilisation by approx. 2-fold and also partially suppressed the preferential mobilisation of C20-22 polyunsaturates. These results may be relevant to the elucidation of the means by which essential polyunsaturates are delivered from the yolk to the neural tissues of the embryo, with the implication of a mediatory role for the embryonic adipose tissue in this transfer.

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Nutritional Values – Parmigiano Reggiano

Also see:
Parmigiano Reggiano cheese and bone health

Source 

Parmigiano-Reggiano is a complete, genuine nutriment, a real nourishing food, and it’s the right answer for an healthy and balanced nourishment. In Parmigiano-Reggiano there’s a real concentration of nutritive elements: just think that to make one kilogram of cheese, 16 litres of high quality milk are needed. To make the importance of this nutriment clear, you should know that 100 grams of Parmigiano-Reggiano are equivalent nutritively to:

300 grams beef steak.gif (6164 byte)
700 grams trout trota2.gif (6310 byte)
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The calories value is 392 cal/hg.
But there are many more qualities that make this food really exceptional and unique: 

COMPOSITION OF PARMIGIANO REGGIANO
(referred to 100 g cheese)
Humidity g. 30.8
total proteins g. 33.0
lipides g. 28.4
calcium g. 1.16
phosphorous g. 0.68
calcium / phosphorous ratio 1.71
sodium chloride g. 1.39
magnesium g. 43 . 10-3
zinc g. . 10-3
vitamin A g. 298 . 10-6
vitamin B1 g. 32 . 10-6
vitamin B2 g. 370. 10-6
vitamin B6 g. 106 . 10-6
vitamin B12 g. 4.2 . 10-6
choline g. 42 . 10-3
biotin g. 22 . 10-6

Digestibility– Parmigiano-Reggiano is a “simplified digestion” food; it contains in fact 7,5% of free amino acids (a quantity that is decidedly larger than any other kind of cheese) that can be assimilated and absorbed by the organism without any digestion process. Moreover it stimulates the gastric production thus helping to digest other foods, too. That’s why it is useful and correct eating flakes of Parmigiano-Reggiano as hors-d’oeuvre or at the end of the meal. 100 grams of Parmigiano-Reggiano are assimilated in 45 minutes (contrary to, for instance, 4 hours needed for the same quantity of meat).

Proteins– Thanks to its high protein contribution (the protein content is about 35%), Parmigiano-Reggiano can offer an important contribution to diet, moreover the protein quality is similar to vegetal protein one.

Vitamins – Milk and cheese in our food share are not aliments that can satisfy our daily vitamin needs. However 100 grams of Parmigiano-Reggiano can cover about 40% of Vitamin A daily needs and 20% of Vitamin B2, while they provide for a far larger quantity of Vitamin B12 than the physiological needs. In general, the vitamin content of Parmigiano – Reggiano is on average larger, especially as far as beta-carotene, Vitamin A, B2, B6, B12 are concerned, compared to the content of other kinds of cheese. These vitamins are important both for growing and for a protective and anti-toxic action, thus helping the formation of antibodies and defence against polluting agents that are increasingly present in the environment.

It is a non fat type of cheese – the fat content (about 20%) is the lowest compared to all other types of cheese with the exception of “mozzarella” (milky buffalo cheese) and stracchino; moreover the maturing process transforms these fats thus making them easily absorbable by the organism.

sport.jpg (22335 byte)The experts of sportsmen diets recommend the use of Parmigiano-Reggiano because of its easy digestion; moreover thanks to its extraordinary properties it becomes a natural food integrator, necessary for those who go in for a sport and especially if it’s a sport of strength like wrestling, weight-lifting, boxing. It is not by chance that in the special diet of Olympic athletes Parmigiano-Reggiano plays an important role.

Excellent also for children and elderly people. Pediatrists recommend it as a nutriment for children because of its protein, vitamin and calcium abundance and digestibility which are extremely useful for children growth. It’s proved scientifically that after a 15-18 months maturing, enzymes without additives, have a therapeutic action in treating viral and bacterial enteritis typical of children in the first months of life, so much so that it can also replace antibiotics normally prescribed for those illnesses. Parmigiano-Reggiano is also recommended for elderly people thanks to its large content of phosphorous and calcium (indispensable to fight osteoporosis) and for its digestibility that makes it easily absorbable.

 

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Factors That Can Lower TSH

Aging, infection, trauma, prolonged cortisol excess, somatostatin, dopamine or L-dopa, adrenaline (sometimes; Mannisto, et al., 1979), amphetamine, caffeine and fever can lower TSH, apart from the effect of feedback by the thyroid hormones, creating a situation in which TSH can appear normal or low, at the same time that there is a real hypothyroidism. -Ray Peat, PhD

Acta Endocrinol (Copenh). 1979 Feb;90(2):249-58.
Dual action of adrenergic system on the regulation of thyrotrophin secretion in the male rat.
Männistö, Ranta T, Tuomisto J.
The effect of graded doses of drugs modifying adrenergic activity on basal and cold-stimulated TSH secretion was studied in male rats. alpha-methyl-p-tyrosine (aMPT) (16 h before 30 min cold-exposure), phenoxybenzamine (1 h), Ca-fusarate (1 h) and diethyldithiocarbamate (DDC) (1 and 18 h) dose-dependently depressed the cold-stimulated TSH secretion. The effect of reserpine (24 h) was not significant. Clonidine (1 h), dihydroxyphenyl-serine (DOPS) (1 h), noradrenaline (NA) (1 h), and L-Dopa (1 h) were also effective in decreasing serum TSH levels, but dopamine (DA) (ad 2 mg/kg, 1 h) had no effect. Basal TSH levels were also decreased by various doses of clonidine, DOPS and NA, given ip 1 h before sacrifice. Clonidine (1 mg/kg), NA (1 mg/kg), DA (2 mg/kg), aMPT (300 mg/kg), phenoxybenzamine (2 or 20 mg/kg), Ca-fusarate (50 mg/kg) or L-Dopa (200 mg/kg) did not modify the TRH-induced TSH response. These results cannot be explained by assuming only a stimulatory function for the adrenergic system on the secretion of TSH in the rat. The site of the possible inhibitory function of noradrenaline in the control of TSH cannot be deduced from these results, but various possibilities are discussed.

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