|
50 years ago, in the first phase of marketing the polyunsaturated fatty acids (PUFA), linoleic acid was “heart protective,” and the saturated fats raised cholesterol and caused heart disease.
In the second phase, the other “essential fatty acid,” linolenic acid, was said to be even better than linoleic acid.
In the third phase, the longer chain omega -3 (omega minus three, or n minus three) fatty acids, DHA and EPA, are said to be even better than linolenic acid.
Along the way, the highly unsaturated arachidonic acid, which we and other animals make out of the linoleic acid in foods, was coming to be identified with the “harmful animal fats.” But we just didn’t hear much about how the amount of arachidonic acid in the tissues depended on the amount of linoleic acid in the diet.
U.S. marketing dominates the world economy, including of course the communication media, so we shouldn’t expect to hear much about the role of PUFA in causing cancer, diabetes, obesity, aging, thrombosis, arthritis and immunodeficiency, or to hear about the benefits of the saturated fats.
The saturated fats include the “tropical fats,” because they are synthesized in very warm organisms, and are very stable at those temperatures. Their stability offers some protection against the unstable PUFA.
Several of the degenerative conditions produced by the 'essential fatty acids' can be reversed by use of saturated fats, varying in length from the short chains of coconut oil to the very long chains of waxes.
When a person uses a drug, there is generally an awareness that the benefit has to be weighed against the side effects. But if something is treated as a “nutrient,” especially an “essential nutrient,” there is an implication that it won’t produce undesirable side effects.
Over the last thirty years I have asked several prominent oil researchers what the evidence is that there is such a thing as an “essential fatty acid.” One professor cited a single publication about a solitary sick person who recovered from some sickness after being given some unsaturated fat. (If he had known of any better evidence, wouldn’t he have mentioned it?) The others (if they answered at all) cited “Burr and Burr, 1929.” The surprising thing about that answer is that these people can consider any nutritional research from 1929 to be definitive. It’s very much like quoting a 1929 opinion of a physicist regarding the procedure for making a hydrogen bomb. What was known about nutrition in 1929? Most of the B vitamins weren’t even suspected, and it had been only two or three years since “vitamin B” had been subdivided into two factors, the “antineuritic factor,” B1, and the “growth factor,” B2. Burr had no way of really understanding what deficiencies or toxicities were present in his experimental diet.
A few years after the first experiments, Burr put one of his “essential fatty acid deficient” rats under a bell jar to measure its metabolic rate, and found that the deficient animals were metabolizing 50% faster than rats that were given linoleic and linolenic acids as part of their diet. That was an important observation, but Burr didn’t understand its implications. Later, many experiments showed that the polyunsaturated fats slowed metabolism by profoundly interfering with the function of the thyroid hormone and the cellular respiratory apparatus. Without the toxic fats, respiratory energy metabolism was very intense, and a diet that was nutritionally sufficient for a sluggish animal wouldn’t necessarily be adequate for the vigorous animals.
Several publications between 1936 and 1944 made it very clear that Burr’s basic animal diet was deficient in various nutrients, especially vitamin B6. The disease that appeared in Burr’s animals could be cured by fat free B-vitamin preparations, or by purified vitamin B6 when it became available. A zinc deficiency produces similar symptoms, and at the time Burr did his experiments, there was no information on the effects of fats on mineral absorption. If a diet is barely adequate in the essential minerals, increasing the metabolic rate, or decreasing intestinal absorption of minerals, will produce mineral deficiencies and metabolic problems.
Although “Burr’s disease” clearly turned out to be a B-vitamin deficiency, probably combined with a mineral deficiency, it continues to be cited as the basis justifying the multibillion dollar industry that has grown up around the “essential” oils.
Two years before Burr’s experiment, German researchers found that a fat-free diet prevented almost all spontaneous cancers in rats. Later work showed that the polyunsaturated fats both initiate and promote cancer. With that knowledge, the people who kept claiming that “linoleic, linolenic, and maybe arachidonic acid are the essential fatty acids,” should have devoted some effort to finding out how much of that “essential nutrient” was enough, so that people could minimize their consumption of the carcinogenic stuff.
Between the first and second world wars, cod liver oil was recommended as a vitamin supplement, at first as a source of vitamin A, and later as a source of vitamins A and D. But in the late 1940s, experimenters used it as the main fat in dogs’ diet, and found that they all died from cancer, while the dogs on a standard diet had only a 5% cancer mortality. That sort of information, and the availability of synthetic vitamins, led to the decreased use of cod liver oil.
But around that time, the seed oil industry was in crisis because the use of those oils in paints and plastics was being displaced by new compounds made from petroleum. The industry needed new markets, and discovered ways to convince the public that seed oils were better than animal fats. They were called the “heart protective oils,” though human studies soon showed the same results that the animal studies had, namely, that they were toxic to the heart and increased the incidence of cancer.
The “lipid hypothesis” of heart disease argued that cholesterol in the blood caused atherosclerosis, and that the polyunsaturated oils lowered the amount of cholesterol in the blood. Leaving behind the concept of nutritional essentiality, this allowed the industry (and their academic supporters, such as Frederick Stare at Harvard) to begin promoting the oils as having drug-like therapeutic properties. Larger amounts of polyunsaturated fat were supposed to be more protective by lowering the cholesterol, and were to be substituted for the saturated fats, which supposedly raised cholesterol and increased heart disease, producing atherosclerotic plaques in the blood vessels and increasing the formation of blood clots.
Since all ordinary foods contain significant amounts of the polyunsaturated fats, there was no reason to think that, even if they were essential nutrients, people were likely to become deficient in them. So the idea of treating the seed oils as drug-like substances, to be taken in large amounts, appealed to the food oil industry.
Prostaglandins, which are produced in the body by oxidizing the polyunsaturated fatty acids, provided an opportunity for the drug industry to get involved in a new market, and the prostaglandins offered a new way of arguing for the nutritional essentiality of linoleic and related acids: A whole system of “hormones” is made from these molecules. Since some of the prostaglandins suppress immunity, cause inflammation and promote cancer growth, some people have divided them into the “good prostaglandins” and the “bad prostaglandins.”
PGI2, or prostacyclin, is considered to be a good prostaglandin, because it causes vasodilatation, and so drug companies have made their own synthetic equivalents: Epoprostenol, iloprost, taprostene, ciprostene, UT-15, beraprost, and cicaprost. Some of these are being investigated for possible use in killing cancer.
But many very useful drugs that already existed, including cortisol and aspirin, were found to achieve some of their most important effects by inhibiting the formation of the prostaglandins. It was the body’s load of polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation, hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the activation of the stored “essential fatty acids,” gain their remarkable range of beneficial effects partly by the restraint they impose on those stored toxins.
Increasingly, the liberation of arachidonic acid from tissues during stress is seen as a central factor in all forms of stress, both acute (as in burns or exercise) or chronic (as in diabetes or aging). And, as the fat stores become more toxic, it seems that they more readily liberate the free fatty acids. (For example, see Iritani, et al., 1984)
During this same period, a few experimenters were finding that animals which were fed a diet lacking the “essential” fatty acids had some remarkable properties: They consumed oxygen and calories at a very high rate, their mitochondria were unusually tough and stable, their tissues could be transplanted into other animals without provoking immunological rejection, and they were very hard to kill by trauma and a wide variety of toxins that easily provoke lethal shock in animals on the usual diet. As the Germans had seen in 1927, they had a low susceptibility to cancer, and new studies were showing that they weren’t susceptible to various fibrotic conditions, including alcoholic liver cirrhosis.
In 1967 a major nutrition publication, Present Knowledge in Nutrition, published Hartroft and Porta’s observation that the “age pigment,” lipofuscin, was formed in proportion to the amount of polyunsaturated fat and oxidants in the diet. The new interest in organ transplantation led to the discovery that the polyunsaturated fats prolonged graft survival, by suppressing the immune system. Immunosuppression was considered to have a role in the carcinogenicity of the “essential” fatty acids.
Around the same time, there were studies that showed that unsaturated fats retarded brain development and produced obesity.
Substances very much like the prostaglandins, called isoprostanes and neuroprostanes, are formed spontaneously from highly unsaturated fatty acids, and are useful as indicators of the rate of lipid peroxidation in the body. Most of the products of lipid peroxidation are toxic, as a result of their reactions with proteins, DNA, and the mitochondria. The age-related glycation products that are usually blamed on sugar, are largely the result of peroxidation of the polyunsaturated fatty acids.
Through the 1970s, this sort of information about the harmful effects of the PUFA was being slowly assimilated by the culture, though many dietitians still spoke of “the essential fatty acids, vitamin F.” By 1980, it looked as though responsible researchers would see the promotion of cancer, heart disease, mitochondrial damage, hypothyroidism and immunosuppression caused by the polyunsaturated fats as their most important feature, and would see that there had never been a basis for believing that they were essential nutrients.
But then, without acknowledging that there had been a problem with the doctrine of essentiality, fat researchers just started changing the subject, shifting the public discourse to safer, more profitable topics. The fats that had been called essential, but that had so many toxic effects, were no longer emphasized, and the failed idea of “essentiality” was shifted to different categories of polyunsaturated fats.
The addition of the long chain highly unsaturated fats to baby food formulas was recently approved, on the basis of their supposed “essentiality for brain development.” One of the newer arguments for the essentiality of the PUFA is that “they are needed for making cell membranes.” But human cells can grow and divide in artificial culture solutions which contain none of the polyunsaturated fats, and no one has claimed that they are growing “without membranes.”
The long chain fats found in fish and some algae don’t interfere with animal enzymes as strongly as the seed oils do, and so by comparison, they aren’t so harmful. They are also so unstable that relatively little of them is stored in the tissues. (And when they are used as food additives, it’s necessary to use antioxidants to keep them from becoming smelly and acutely toxic.)
When meat is grilled at a high temperature, the normally spaced double bonds in PUFA migrate towards each other, becoming more stable, so that linoleic acid is turned into “conjugated linoleic acid.” This analog of the “essential” linoleic acid competes against the linoleic acid in tissues, and protects against cancer, atherosclerosis, inflammation and other effects of the normal PUFA. Presumably, anything which interferes with the essential fatty acids is protective, when the organism contains dangerous amounts of PUFA. Even the trans-isomers of the unsaturated fatty acids (found in butterfat, and convertible into conjugated linoleic acid) can be protective against cancer.
In the 1980s the oil promoters were becoming more sophisticated, and were publishing many experiments in which the fish oils were compared with corn oil, or safflower, or soy oil, and in many of those experiments, the animals’ health was better when they didn’t eat the very toxic seed oils, that contained the “essential fatty acids,” linoleic and linoleic acids.
Besides comparing the fish oils to the stronger toxins, another trick is to take advantage of the same immunosuppressive property that had seemed troublesome, and to emphasize their ability to temporarily alleviate some autoimmune or allergic diseases. X-rays were once used that way, to treat arthritis and ringworm, for example.
And, knowing that cancer cells have the ability to consume large amounts of fatty acids, they would test these fats in tissue culture dishes, and demonstrate that they were poisonous, cytotoxic, to the fast growing cancer cells. Although they caused cancer in animals, if they could be shown to kill cancer cells in a dish, they could be sold as anticancer drugs/nutrients, with the special mystique of being “essential fatty acids.” Strangely, their ability to kill cancer cells under some circumstances and to suppress some immunological reactions is being promoted in close association with the doctrine that these fats are nutritionally essential.
Arachidonic acid is made from linoleic acid, and so those two oils were considered as roughly equivalent in their ability to meet our nutritional needs, but a large part of current research is devoted to showing the details of how fish oils protect against arachidonic acid. The “balance” between the omega -3 and the omega -6 fatty acids is increasingly being presented as a defense against the toxic omega -6 fats. But the accumulation of unsaturated fats with aging makes any defense increasingly difficult, and the extreme instability of the highly unsaturated omega -3 fats creates additional problems.
PUFA and x-rays have many biological effects in common. They are immunosuppressive, but they produce their own inflammatory reactions, starting with increased permeability of capillaries, disturbed coagulation and proteolysis, and producing fibrosis and tumefaction or tissue atrophy. This isn’t just a coincidence, since ionizing radiation attacks the highly unstable polyunsaturated molecules, simply accelerating processes that ordinarily happen more slowly as a result of stress and aging.
Prolonged stress eventually tends to be a self-sustaining process, impairing the efficient respiratory production of energy, converting muscle tissue to amino acids, suppressing the thyroid, and activating further mobilization of fatty acids. Fatty acids are mobilized from within the structure of cells by phospholipases, and from fat tissues by other lipases.
The highly unsaturated fatty acids, as well as the ordinary “essential fatty acids,” act directly to increase capillary permeability, even without conversion into prostaglandins, and they interefere in many ways with the clotting and clot removal systems. The effects of PUFA taken in a meal probably disturb the clotting system more than the same quantity of saturated fat, contrary to many of the older publications. The PUFA are widely believed to prevent clotting, but when cod liver oil is given to “EFA deficient” animals, it activates the formation of clots (Hornstra, et al., 1989). An opposite effect is seen when a long chain fatty acid synergizes with aspirin, to restrain clotting (Molina, et al., 2003).
Fibrosis is a generalized consequence of the abnormal capillary permeability produced by things that disrupt the clotting system. Estrogen, with its known contribution to the formation of blood clots and edema and fibrosis and tumors, achieves part of its effect by maintaining a chronically high level of free fatty acids, preferentially liberating arachidonic acid, rather than saturated fatty acids.
Butter, beef fat, and lamb fat are the only mostly saturated fats produced on a large scale in the U.S., and the cheapness/profitability of the seed oils made it easy to displace them. But, in the face of the immense amount of propagandistic “health” claims that have been made against the saturated fats, it’s instructive to look at some of their actual effects, especially on the clotting system, and the related fibrotic reactions.
The saturated fatty acids are very unreactive chemically. Coconut oil, despite containing about 1% of the unstable PUFA, can be left in a bucket at room temperature for a year or more without showing any evidence of deterioration, suggesting that the predominance of saturated fat acts as an antioxidant for the unsaturated molecules. In the body, the saturated fats seem to act the same way, preventing or even reversing many of the conditions caused by oxidation of fats.
The stress-induced liberation of arachidonic acid causes blood vessels to leak, and this allows fibrin to escape from the blood stream, into the basement membrane and beyond into the extracellular matrix, where it produces fibrosis. (Cancer, autoimmune diseases, and heart disease involve the same inflammatory, thrombotic, fibrotic processes as the nominal fibroses.) Scleroderma, liver cirrhosis, fibrosis of the lungs, heart, and other organs, and all the diseases in which fibrous tissue becomes dense and progressively contracts, involve similar processes, and the treatments which are successful are those that stop the inflammation produced by the oxidation of the polyunsaturated fatty acids.
Retroperitoneal fibrosis is now known to be produced by estrogen, and is treated by antiestrogenic and antiserotonergic drugs, but as early as 1940 Alejandro Lipschutz demonstrated that chronic exposure to very low doses of estrogen produced fibromas in essentially every part of the body. Earlier, Loeb had studied the action of large doses of estrogen, which produced fibrosis of the uterus, as if it had accelerated aging. Following Lipschutz’ work, in which he demonstrated the “antifibromatogenic” actions of pregnenolone and progesterone, several Argentine researchers showed that progesterone prevented and cured abdominal adhesions and other fibrotic conditions, including retroperitoneal fibrosis.
Since estrogen produces both leakiness of the capillaries and excessive formation of fibrin, its effects will be seen first in the organs where it concentrates, but eventually anywhere capillaries leak fibrin. Estrogen activates the phospholipase which liberates arachidonic acid, and progesterone inhibits that phospholipase.
As the fat tissues become more burdened with arachidonic acid, they release it more easily in response to moderately lipolytic stress signals. This could explain the increased levels of free fatty acids and lipid peroxidation that occur with aging. In animals that are “deficient” in the polyunsaturated fatty acids, adrenalin doesn’t have the lipolytic effect that it does in animals on the standard diet. With aging, there is not only a tendency to have chronically higher free fatty acids in the blood, but for those fatty acids to be more unsaturated. The phospholipids of mitochondria and microsomes become more unsaturated with aging (Laganiere and Yu, 1993, Lee, et al., 1999). In the human retina there is a similar accumulation of PUFA with aging (Nourooz-Zadeh and Pereira, 1999), which implies that the aged retina will be more easily damaged by light.
Several studies suggest that a high degree of unsaturation in the fats is fundamentally related to the aging process, since long lived species have a lower degree of unsaturation in their fats. Caloric restriction decreases the age-related accumulation of the fatty acids with 4 and 5 double bonds.
Although publicity has emphasized the antiinflammatory effects of fish oil, experiments show that it is extremely effective in producing alcohol-related liver cirrhosis. Breakdown products of polyunsaturated fats (isoprostanes and 4-HNE) are found in the blood of people with alcoholic liver disease (Aleynik, et al., 1998). In the absence of polyunsaturated fats, alcohol doesn’t produce cirrhosis. Saturated fats allow the fibrosis to regress:
“A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation....” (Nanji, et al., 1995, 2001)
In these studies, the animals were switched from fish oil to either palm oil or medium chain triglycerides (a major fraction of coconut oil). In other studies, Knittel, et al. (1995), show that fibrinogen, in “a clotting-like process,” is involved in the development of liver fibrosis, and that this appears to provide a basis for the growth of additional extracellular matrix.
Brown, et al. (1989), discussed this developmental process (leaky capillaries, fibrosis) in relation to wound healing, lung disease, and tumor growth.
The relatively few studies of fish oil and linoleic acid that compare them with palmitic acid or coconut oil have produced some very important results. For example, pigs exposed to endotoxin developed severe lung problems (resembling “shock lung”) when they had been on a diet with either fish oil or Intralipid (which is mostly linoleic acid, used for intravenous feeding in hospitals), but not after palmitic acid (Wolfe, et al., 2002).
Eating low-fat seafood (sole, whitefish, turbot, scallops, oysters, lobster, shrimp, squid, etc.) once in a while can provide useful trace minerals, without much risk. However, fish from some parts of the ocean contain industrial contaminants in the fat, and large fish such as tuna, swordfish, Chilean sea bass and halibut contain toxic amounts of mercury in the muscles. Chilean sea bass (Patagonian toothfish) is very high in fat, too.
About ten years ago I met a young man with a degenerative brain disease, and was interested in the fact that he (working on a fishing boat) had been eating almost a pound of salmon per day for several years. There is now enough information regarding the neurotoxic effects of fish oil to justify avoidance of the fatty fish.
Some of the current advertising is promoting fish oil to prevent cancer, so it’s important to remember that there are many studies showing that it increases cancer.
The
developmental and physiological significance of the type of fatty acid
in the diet has been established for a long time, but cultural stereotypes
and commercial interests are threatened by it, so it can’t be discussed
publicly.
REFERENCES
Alcohol Clin Exp Res 1998 Feb;22(1):192-6. Increased circulating
products of lipid peroxidation in patients with alcoholic liver disease.
Aleynik SI, Leo MA, Aleynik MK, Lieber CS
Ann N Y Acad Sci. 1976;275:28-46. Metabolic influences in experimental
thrombosis. Antoniades HN, Westmoreland N.
Nutr Cancer. 2001;41(1-2):91-7. Vaccenic acid feeding increases tissue
levels of conjugated linoleic acid and suppresses development of premalignant
lesions in rat mammary gland. Banni S, Angioni E, Murru E, Carta
G, Melis MP, Bauman D, Dong Y, Ip C.
Obstet Gynecol. 1987 Sep;70(3 Pt 2):502-4. The treatment of
retroperitoneal fibromatosis with medroxyprogesterone acetate. Barnhill
D, Hoskins W, Burke T,
Weiser E, Heller P, Park R. Wide excision is the recommended primary
therapy for retroperitoneal fibromatosis. Radiation therapy and a variety
of medications have been used to treat patients with recurrent tumors,
but the response to these agents has not been uniform. The patient presented
was successfully treated with medroxyprogesterone acetate for recurrent
retroperitoneal fibromatosis that was refractory to multiple operative
resections and radiation therapy.
Medicina (B Aires). 1978 Mar-Apr;38(2):215-6. [Fibromatosis, relaxin and progesterone] [in Spanish] Barousse AP. [Letter]
Medicina (B Aires). 1985;45(2):159-63. Progesterone as therapy for
retroperitoneal fibrosis. Bilder CR, Barousse AP, Mazure PA.
Adv Exp Med Biol. 1976;75:497-503.
Effect of ionizing radiation on liver
microcirculation and oxygenation. Bicher HI, Dalrymple GV, Ashbrook
D, Smith R, Harris D.
Lipids. 1981 May;16(5):323-7. Iodination of
docosahexaenoic acid by lactoperoxidase and thyroid gland in vitro:
formation of an lodolactone. Boeynaems JM, Watson JT, Oates JA,
Hubbard WC. “In the presence
of iodide, hydrogen peroxide and lactoperoxidase, docosahexaenoic acid
(22:6 omega 3) was converted into iodinated compounds.”
Am Rev
Respir Dis 1989 Oct;140(4):1104-7. Leaky vessels, fibrin deposition,
and fibrosis: a sequence of events common to
solid tumors and to many other types of disease. Brown LF, Dvorak
AM, Dvorak HF
Medicina (B Aires). 1979 Sep-Oct;39(5):652-4. [Effect of progesterone
in the treatment of a patient with idiopathic retroperitoneal fibrosis]
[in Spanish] Casadei DH, Najun Zarazaga C, Leanza HJ, Schiappapietra
JH.
Biochem
Mol Biol Int 1993 Jan;29(1):175-83. Influence of antioxidant vitamins
on fatty acid inhibition of lymphocyte proliferation. Calder PC,
Newsholme EA. “Vitamin E (10 microM) increased human lymphocyte proliferation
by 35%. However, vitamin E did not prevent the inhibitory effects of
fatty acids upon lymphocyte proliferation. It is concluded that inhibition
of lymphocyte proliferation by fatty acids is not caused by their conversion
to peroxidised products.”
Clin Sci (Lond). 1992 Jun;82(6):695-700. Polyunsaturated fatty
acids suppress human peripheral blood lymphocyte proliferation and interleukin-2 production. Calder
PC, Newsholme EA.
J Neurochem
1980 Oct;35(4):1004-7. Transient formation of
superoxide radicals in polyunsaturated fatty acid-induced brain swelling.
Chan PH, Fishman RA
Int J Cancer 2001 Mar 15;91(6):894-9. Tumor invasiveness and liver
metastasis of colon cancer cells correlated with
cyclooxygenase-2 (COX-2) expression and inhibited by a
COX-2-selective inhibitor, etodolac. Chen
WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK.
Free
Radic Biol Med. 1999 Jul;27(1-2):51-9. Arachidonic acid interaction
with the mitochondrial electron transport chain promotes reactive oxygen
species generation. Cocco T, Di Paola M, Papa S, Lorusso M.
Clin Exp Metastasis 1997 Jul;15(4):410-7. Influence of lipid diets
on the number of metastases and ganglioside content of H59 variant tumors.
Coulombe J, Pelletier G, Tremblay P, Mercier G, Oth D.
BJU Int. 2003 Jun;91(9):830-8. Fibrin as an inducer of fibrosis in the tunica albuginea of the rat: a new animal model of Peyronie's disease. Davila HH, Ferrini MG, Rajfer J, Gonzalez-Cadavid NF.
Carcinogenesis
1994 Jul;15(7):1399-404. Peroxidation
of linoleic, arachidonic and oleic acid in relation to the induction
of oxidative DNA damage and cytogenetic effects. de Kok TM, ten
Vaarwerk F, Zwingman I, van Maanen JM, Kleinjans JC.
Biochem
Biophys Res Commun. 2000 Oct 14;277(1):128-33. Arachidonic acid causes
cytochrome c release from heart mitochondria. Di Paola M, Cocco
T, Lorusso M.
J Physiol. 1998 Mar 1;507 ( Pt 2):541-7. Arachidonic
acid increases cerebral microvascular permeability by free radicals
in single pial microvessels of the anaesthetized rat.
Easton AS, Fraser PA.
Am J Physiol. 1992 May;262(5 Pt 1):E637-43. ATP depletion stimulates calcium-dependent protein breakdown in chick skeletal Muscle. Fagan JM, Wajnberg EF, Culbert L, Waxman L.
Cancer Res 1998 Aug 1;58(15):3312-9. Dietary omega-3 polyunsaturated fatty acids promote colon carcinoma metastasis in rat liver. Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W, Smorenburg SM, Van Noorden CJ.
J Indian Med Assoc 1997 Mar;95(3):67-9, 83. Association of dietary ghee intake with coronary heart disease and risk factor prevalence in rural males. Gupta R, Prakash H
Transplantation 1995 Sep 27;60(6):570-7. The effect of dietary polyunsaturated
fatty acids (PUFA) on acute rejection and cardiac
allograft blood flow in rats. Haw MP, Linnebjerg H, Chavali SR,
Forse RA. “The immunosuppressive effect of dietary PUFA warrants further
investigation, and their use as a possible adjunctive treatment in organ
transplantation should be considered.”
Dtsch Med Wochenschr. 2003 Jun 20;128(25-26):1395-8. [Rare
cause of chronic abdominal pain: retractile
mesenteritis] [in German] Hermann F, Speich R, Schneemann M. “Retractile
mesenteritis is a rare cause of chronic abdominal pain with variable
symptoms. Its aetiology is unknown. In case of bowel ischemia a surgical approach is preferred,
milder forms may be treated with immunosuppressive agents as well as
oral progesterone. Progesterone has exhibited positive effects on fatty
tissue with successful treatment in desmoid tumors and retroperitoneal
fibrosis. Here in we could demonstrate its safe and efficient use in
a patient with retractile mesenteritis.”
Mech Ageing Dev 2001 Apr 15;122(4):427-43. Effect of the degree
of fatty acid unsaturation of rat heart mitochondria on their rates
of H2O2 production and lipid and protein oxidative damage. Herrero
A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G. “Previous comparative
studies have shown that long-lived animals have lower fatty acid double
bond content in their mitochondrial membranes than short-lived ones.
In order to ascertain whether this trait protects mitochondria by decreasing
lipid and protein oxidation and oxygen radical generation, the double
bond content of rat heart mitochondrial membranes was manipulated by
chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated
(UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly
higher double bond content and lipid peroxidation than SAT mitochondria.
They also showed increased levels of the markers of protein oxidative
damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine
adducts.” “These results demonstrate that increasing the degree
of fatty acid unsaturation of heart mitochondria increases oxidative
damage to their lipids and proteins, and can also increase their rates
of mitochondrial oxygen radical generation in situations in which the
degree of reduction of Complex III is higher than normal. These observations
strengthen the notion that the relatively low double bond content of
the membranes of long-lived animals could have evolved to protect them
from oxidative damage.”
Biochem J. 1994 May 15;300 ( Pt 1):251-5. Regulation
of fibrinolysis by non-esterified fatty acids. Higazi AA, Aziza
R, Samara AA, Mayer M. “Examination of the fatty acid specificity
showed that a minimal chain length of 16 carbon atoms and the presence
of at least one double bond, preferably in a cis configuration, were
required for inhibition of the fibrinolytic activity of plasmin.”
Science. 1976 Feb 27;191(4229):861-2. Nicotinic acid reduction of plasma volume loss after thermal trauma. Hilton JG, Wells CH. Intravenous administration of nicotinic acid to the anesthetized dog prior to thermal trauma reduced plasma loss at 10 minutes after burn from 7 milliliters per kilogram to less than 2 millimeters per kilogram. During the next 50 minutes plasma loss was the same in treated and untreated animals. An additional dose of nicotinic acid 30 minutes after burn prevented this further loss.
Z Gesamte Inn Med. 1976 Oct 15;31(20):838-43. [Age-dependence of catecholamine effects in man. IV. Effects of specific inhibitors on the lipolytic action of alpha and beta adrenergics] [in German] Hoffmann H.
Neurochem Res. 2000 Feb;25(2):269-76. Cortical impact injury in rats promotes a rapid and sustained increase in polyunsaturated free fatty acids and diacylglycerols. Homayoun P, Parkins NE, Soblosky J, Carey ME, Rodriguez de Turco EB, Bazan NG. “At day one, free 22:6 and 22:6-DAGs showed the greatest increase (590% and 230%, respectively). These results suggest that TBI elicits the hydrolysis of phospholipids enriched in excitable membranes, targeting early on 20:4-phospholipids (by 30 min post- trauma) and followed 24 hours later by preferential hydrolysis of DHA-phospholipids. These lipid metabolic changes may contribute to the initiation and maturation of neuronal and fiber track degeneration observed following cortical impact injury.”
Thromb Res. 1989 Jan 1;53(1):45-53. Normalization by dietary cod-liver oil of reduced thrombogenesis in essential fatty acid deficient rats. Hornstra G, Haddeman E, Don JA.
Radiographics. 2003 Nov-Dec;23(6):1561-7. CT Findings in Sclerosing Mesenteritis (Panniculitis): Spectrum of Disease. Horton KM, Lawler LP, Fishman EK.
Nutr Cancer. 1985;7(4):199-209. Isomeric fatty acids and tumorigenesis: a commentary on recent work. Hunter JE, Ip C, Hollenbach EJ. “Neither epidemiological nor experimental studies published to date have demonstrated any valid association between trans fatty acid ingestion and tumorigenesis. A recent study showed that under controlled conditions, a fat with a high content of trans fatty acids did not promote the development of mammary tumors induced in rats by 7,12-dimethylbenz[a]anthracene to any greater extent than did a comparable fat with a high content of cis fatty acids. In addition, in this study a high trans fat was less tumor promoting than was a blend of fats that simulated the dietary fat composition of the United States and had a lower level of trans fatty acids.”
Medicina (B Aires). 1978 Mar-Apr;38(2):215. [Progesterone and retroperitoneal fibrosis] [in Spanish] Introzzi A.[Letter]
Cancer Res. 1985 May;45(5):1997-2001. Requirement of essential fatty acid for mammary tumorigenesis in the rat. Ip C, Carter CA, Ip MM. “Mammary tumorigenesis was very sensitive to linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary linoleate.”
Biochim Biophys Acta. 1984 Nov 6;802(1):17-23. Activation of bovine platelets induced by long-chain unsaturated fatty acids at just below their lytic concentrations, and its mechanism. Kitagawa S, Endo J, Kametani F.
Clin Exp Metastasis 2000;18(5):371-7. Promotion of colon cancer metastases in rat liver by fish oil diet is not due to reduced stroma formation. Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM. “Recently, it was demonstrated that dietary omega-3 polyunsaturated fatty acids (PUFAs) induce 10-fold more metastases in number and 1000-fold in volume in an animal model of colon cancer metastasis in rat liver.”
Folia Haematol Int Mag Klin Morphol Blutforsch. 1977;104(1):1-10. [Review: hemorrhagic diathesis resulting from acute exposure to ionizing Radiation] [Article in German] Krantz S, Lober M. The symptoms of the acute radiopathy are chiefly characterized by a severe blood coagulation disorder. The main results and problems of research work on this haemorrhagic diathesis are shortly reviewed.
Prostaglandins. 1978 Apr;15(4):557-64. Prostaglandin I2 as a potentiator of acute inflammation in rats. Komoriya K, Ohmori H, Azuma A, Kurozumi S, Hashimoto Y, Nicolaou KC, Barnette WE, Magolda RL.
Gerontology
1993;39(1):7-18. Modulation of membrane
phospholipid fatty acid composition by age and food restriction.
Laganiere S, Yu BP. H.M. “Phospholipids from liver mitochondrial and
microsomal membrane preparations were analyzed to further assess the
effects of age and lifelong calorie restriction on membrane lipid composition.”
“The data revealed characteristic patterns of age-related changes
in ad libitum (AL) fed rats: membrane levels of long-chain polyunsaturated
fatty acids, 22:4 and 22:5, increased progressively, while membrane
linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell
by approximately 40%, and 22:5 content almost doubled making the
peroxidizability index increase with age.” “We concluded
that the membrane-stabilizing action of long-term calorie restriction
relates to the selective modification of membrane long-chain polyunsaturated
fatty acids during aging.”
Medicina (B Aires). 1978 Mar-Apr;38(2):123-32. [Effective treatment of several types of fibromatosis with progesterone. Fibrous mediastinitis, desmoid tumors, paraneoplastic fibrosis] [in Spanish] Lanari A, Molinas FC, Castro Rios M, Paz RA.
Medicina (B Aires). 1979 Nov-Dec;39(6):826-35. [Progesterone in fibromatosis
and atherosclerosis] [in Spanish] Lanari A.
Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake. Lee J, Yu BP, Herlihy JT. “The fatty acid composition of the mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the differences.” “Considered together, these results suggest that DR maintains the integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid profile.”
Lipids 2001 Jun;36(6):589-93. Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.
Acta Chir Scand. 1976;142(1):20-5. Induction of endogenous fibrinolysis inhibition in the dog. Effect of intravascular coagulation and release of free fatty acids. Lindquist O, Bagge L, Saldeen T. “In all groups subjected to infusion of thrombin an increase in plasma free fatty acids (FFA) was observed. The role of this increase for the development of fibrinolysis inhibition was tested by infusion of norepinephrine alone and in combination with nicotinic acid. Norepinephrine caused an increase of FFA after 2 hours and in urokinase inhibitor activity after 24-48 hours. Both of these were diminished by high doses of nicotinic acid, indicating that the release of FFA rather than intravascular coagulation might be the principal mechanism underlying the occurrence of fibrinolysis inhibition following trauma.”
Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids. Malis CD, Weber PC, Leaf A, Bonventre JV.
Prostaglandins Leukot Essent Fatty Acids 1994 Jul;51(1):33-40. Suppression
of human T-cell growth in vitro by
cis-unsaturated fatty acids: relationship to free radicals and lipid
peroxidation. Madhavi
N, Das UN, Prabha PS, Kumar GS, Koratkar R, Sagar PS.
Clin
Exp Metastasis 1998 Jul;16(5):407-14. Diminution of the development
of experimental metastases produced by
murine metastatic lines in essential fatty acid-deficient host mice.
Mannini A, Calorini L, Mugnai G, Ruggieri S.
Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B, Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.
Journal of Lipid Research, Vol. 44, 271-279, February 2003. Arachidonic acid and prostacyclin signaling promote adipose tissue development : a human health concern? F. Massiera, P. Saint-Marc, J. Seydoux , T. Murata , T. Kobayashi , S. Narumiya , P. Guesnet, Ez-Zoubir Amri, R. Negrel and G. Ailhaud1.
Infection.
1994 Mar-Apr;22(2):106-12. Influence of dietary
(n-3)-polyunsaturated fatty acids on
leukotriene B4 and prostaglandin E2 synthesis and course of experimental
tuberculosis in guinea pigs. Mayatepek
E, Paul K, Leichsenring M, Pfisterer M, Wagner D, Domann M, Sonntag
HG, Bremer HJ.
Biochim Biophys
Acta 1994 Sep 15;1214(2):209-20. Reinvestigation of lipid peroxidation
of linolenic acid. Mlakar A, Spiteller G. “Thus, a great number
of previously unknown lipid peroxidation products was detected. It is
assumed that these compounds also occur--at least as intermediates--in
lipid peroxidation processes in mammalian tissue.”
Prostaglandins
Leukot Essent Fatty Acids.
2003 May;68(5):305-10. Synergistic effect of D-003 and aspirin on
experimental thrombosis models. Molina V, Arruzazabala ML, Carbajal
D, Mas R.
Chem
Res Toxicol. 2001 Apr;14(4):431-7. Defining mechanisms of toxicity
for linoleic acid monoepoxides and
diols in Sf-21 cells. Moran JH, Mon T, Hendrickson TL, Mitchell
LA, Grant DF.
J Biochem (Tokyo). 1977
Aug;82(2):529-33. Effects of free fatty acids on
fibrinolytic activity. Muraoka T, Okuda H. A novel method for the
estimation of fibrinolytic activity is proposed. In this method, a fibrin
clot suspension is used as a substrate (fibrin is known to be a physiological
substrate of plasmin). The fibrin clot suspension was prepared by homogenization
of human fibrin clots. With this method, we found that free fatty
acids inhibited the plasmin activity, and long-chain, unsaturated free
fatty acids had a particularly strong inhibitory action on
plasmin. As regards the mechanism of the inhibitory action, free fatty
acids may not inhibit complex formation between
plasmin and fibirin, but may make it impossible for
plasmin to act on fibrin due to deformation of the surface of the fibrin
clot.
Alcohol Clin Exp Res. 1986 Jun;10(3):271-3. Dietary factors and alcoholic
cirrhosis. Nanji AA, French SW.
Gastroenterology.
1995 Aug;109(2):547-54. Dietary
saturated fatty acids: a novel treatment for alcoholic liver disease.
Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.
J
Pharmacol Exp Ther. 1996 Jun;277(3):1694-700. Medium chain
triglycerides and vitamin E reduce the severity of established experimental
alcoholic liver disease. Nanji AA, Yang EK, Fogt F, Sadrzadeh SM,
Dannenberg AJ.
Hepatology. 1997 Dec;26(6):1538-45. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat. Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.
J Pharmacol Exp Ther. 2001 Nov;299(2):638-44. Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.
Gastroenterology 1995 Apr;108(4):1124-35. Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury. Neubauer K, Knittel T, Armbrust T, Ramadori G “Fibrinogen/fibrin deposition in damaged livers was studied by immunohistology.” “Immunohistology showed striking amounts of fibrinogen and fibrin deposits in pericentral necrotic areas (short-term damage) and within fibrotic septa (long-term damage).” “The results show fibrinogen/fibrin deposition during short-term liver injury and liver fibrogenesis, which may suggest the involvement of a "clotting-like process" in short-term liver damage and liver fibrosis. The data might indicate that fibrin/fibronectin constitute a "provisional matrix," which affects the attraction and proliferation of inflammatory and matrix-producing cells.”
Ophthalmic Res. 1999;31(4):273-9. Age-related accumulation of free
polyunsaturated fatty acids in human retina. Nourooz-Zadeh J, Pereira
P.
Chem Res Toxicol. 2002 Mar;15(3):367-72. Formation of cyclic deoxyguanosine
adducts from omega-3 and omega-6 polyunsaturated fatty acids under oxidative
conditions. Pan J, Chung FL.
Radiobiologiia. 1985 Nov-Dec;25(6):763-7. [Mechanism
of circulatory disorders in animals irradiated at high doses] [in
Russian] Pozharisskaia TD, Vasil'eva TP, Sokolova EN, Alekseeva II.
Some data are reported on pathoanatomical changes, a status of the microcirculatory channel
and the coagulogram of animals affected by high doses of ionizing radiation.
The signs of disseminated intravascular
blood coagulation have been revealed.
J Biol Chem. 1998 May 29;273(22):13605-12. Formation of
isoprostane-like compounds (neuroprostanes) in
vivo from docosahexaenoic acid. Roberts LJ 2nd, Montine
TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, Dettbarn WD, Morrow
JD.
Nutr Cancer 1995;24(1):33-45. Effects of linoleic acid and gamma-linolenic acid on the growth and metastasis of a human breast cancer cell line in nude mice and on its growth and invasive capacity in vitro. Rose DP, Connolly JM, Liu XH
Arch
Toxicol. 1997;71(9):563-74. Impaired cellular immune response in
rats exposed perinatally to Baltic Sea herring oil or
2,3,7,8-TCDD. Ross PS, de Swart RL, van der Vliet H, Willemsen L,
de Klerk A, van Amerongen
G, Groen J, Brouwer A, Schipholt I, Morse DC, van Loveren H, Osterhaus
AD, Vos JG.
Nutr
Cancer 1998;30(2):137-43. Effects of dietary
n-3-to-n-6 polyunsaturated fatty acid ratio on mammary
carcinogenesis in rats. Sasaki T, Kobayashi Y, Shimizu
J, Wada M, In'nami S, Kanke Y, Takita T. “An increase in the n-3/n-6
ratio did not suppress the incidence or reduce the latency of mammary
tumor development. The number and weight of mammary tumors per tumor-bearing
rat tended to be large in the group with an
n-3/n-6 ratio of 7.84 compared with those in the other groups. As the
n-3/n-6 ratios were elevated, the total number and weight of tumors
increased gradually.”
J. Biol. Chem. 1940 132: 539-551. Essential fatty acids, vitamin
B6, and other factors in the cure of rat
acrodynia. H. Schneider, H. Steenbock, and Blanche R. Platz
Science. 1988 May 20;240(4855):1032-3. Essential fatty acid depletion
of renal allografts and prevention of rejection. Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith
JB.
Physiol Bohemoslov. 1990;39(2):125-34. Proportion of individual fatty
acids in the non-esterified (free) fatty acid
(FFA) fraction in
the serum of laboratory rats of different ages. Smidova L, Base
J, Mourek J, Cechova I.
Placenta. 2003 Nov;24(10):965-73. Augmented PLA(2)Activity in Pre-eclamptic
Decidual Tissue-A Key Player in the Pathophysiology of 'Acute Atherosis'
in Pre-eclampsia? Staff AC, Ranheim T, Halvorsen B.
Acta Neurochir Suppl (Wien) 1994;60:20-3. Mechanisms of glial swelling by arachidonic acid. Staub F, Winkler A, Peters J, Kempski O, Baethmann A.
Arch
Biochem Biophys. 1991 Aug 15;289(1):33-8. A possible mechanism of
mitochondrial dysfunction during cerebral
ischemia: inhibition of mitochondrial respiration activity by
arachidonic acid. Takeuchi Y, Morii H, Tamura M, Hayaishi O, Watanabe
Y.
J Drug
Target. 2003 Jan;11(1):45-52. Modulation of tumor-selective vascular
blood flow and extravasation by the stable prostaglandin 12 analogue
beraprost sodium.
Tanaka S, Akaike T, Wu J, Fang J, Sawa T, Ogawa M, Beppu T, Maeda H.
Am J Clin Nutr. 2003 May;77(5):1125-32.
Effect of individual dietary fatty acids on
postprandial activation of blood coagulation factor VII and
fibrinolysis in healthy young men. Tholstrup T, Miller GJ, Bysted
A, Sandstrom B.
Biochem Soc Trans. 2003 Oct;31(Pt 5):1075-9. Regression of pre-established atherosclerosis in the apoE-/- mouse by conjugated linoleic acid. Toomey S, Roche H, Fitzgerald D, Belton O.
Int J Biochem Cell Biol. 2003 May;35(5):749-55. Increased muscle
proteasome activities in rats fed a polyunsaturated fatty acid supplemented
diet. Vigouroux S, Farout L, Clavel S, Briand Y, Briand
M. “Changes in the proteasome system, a dominant actor in protein
degradation in eukaryotic cells, have been documented in a large number
of physiological and pathological conditions.” “With the polyunsaturated
fatty acid enriched diet, the chymotrypsin-like and peptidylglutamylpeptide
hydrolase activities increased by 45% in soleus and extensor digitorum
longus (EDL), and by 90% in the gastrocnemius medialis (GM) muscle.
Trypsin-like activity of the proteasome increased by 250% in soleus,
EDL and GM.” “Proteasome activities and level were less stimulated
with a monounsaturated fatty acid supplemented diet.” “Unsaturated
fatty acids are particularly prone to free radical attack. Thus, we
suggest that alterations in muscle proteasome may result from monounsaturated
and polyunsaturated fatty acid-induced peroxidation, in order to eliminate
damaged proteins.”
J Am Coll Nutr. 2000 Aug;19(4):478S-486S. Conjugated linoleic acid
and bone biology. Watkins
BA, Seifert MF. “Recent
investigations with growing rats given butter fat and supplements
of CLA demonstrated an increased rate of bone formation and reduced
ex vivo bone PGE2 production, respectively.”
Ups
J Med Sci. 1979;84(3):195-201. Effect of nicotinic acid on the
posttraumatic increase in free fatty acids and
fibrinolysis inhibition activity in the rat. Wegener T, Bagge L, Saldeen T. Nicotinic acid effectively
inhibited the posttraumatic increase in both free fatty acids (FFA)
and fibrinolysis inhibition activity (FIA) in the blood in rats, indicating
that FFA might be involved in the posttraumatic increase of FIA. The
FIA in the liver was greater than that in other organs studied and was
increased in the posttraumatic phase. The possible role of the liver
in the posttraumatic increase of FIA is discussed.
Am J
Physiol Regul Integr Comp Physiol. 2001 Mar;280(3):R908-12. CLA reduces
antigen-induced histamine and PGE(2) release from sensitized guinea
pig tracheae. Whigham
LD, Cook EB, Stahl JL, Saban R, Bjorling DE, Pariza MW, Cook ME.
Toxicol Appl Pharmacol 1993 May;120(1):72-9. Essential fatty acid
deficiency in cultured human keratinocytes attenuates toxicity due to
lipid peroxidation. Wey HE, Pyron L, Woolery M.
Nutrition. 2002 Jul-Aug;18(7-8):647-53. Dietary fat composition
alters pulmonary function in pigs. Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE.
Thromb Res. 1997 Nov 1;88(3):283-90. Enhanced blood coagulation and enhanced fibrinolysis during hemodialysis with prostacyclin. Novacek G, Kapiotis S, Jilma B, Quehenberger P, Michitsch A, Traindl O, Speiser W. In the present study the effect of unfractionated heparin (UFH) (Liquemin, 750-1000 IU/h), low molecular weight heparin (LMWH) (Fragmin, 3000-7250 IU bolus), and prostacyclin (Flolan, 5 ng/kg body weight/min) on the activation of blood coagulation and fibrinolysis, induced by polysulfone membrane dialyzers during hemodialysis, was compared. Plasma levels of thrombin-antithrombin III complex (TAT), fibrin split product D-dimer, and plasmin-plasmin inhibitor-complex (PPI) were measured in the arterial and venous line of the dialyzer at the beginning and at 10, 60, 120, and 180 minutes of hemodialysis. Five patients on chronic hemodialysis treatment were investigated in a cross over study. Clinically all three anticoagulation regimen were sufficient for hemodialysis treatment. Using UFH or LMWH TAT, PPI, and D-dimer levels were similar in the venous and the arterial line of the dialyzer. However, during prostacyclin treatment the levels of these activation markers were significantly higher in the venous line. Based on these data the dialyzer membrane can be considered as a site of activation of blood coagulation and of fibrinolysis during anticoagulation with prostacyclin in hemodialysis.
Am J Clin Nutr. 2003 May;77(5):1125-32. Effect of individual dietary fatty acids on postprandial activation of blood coagulation factor VII and fibrinolysis in healthy young men. Tholstrup T, Miller GJ, Bysted A, Sandstrom B. “When the data were pooled, the saturated (S, P, and M) test fats resulted in a smaller postprandial increase in FVIIa (P = 0.036, diet effect), a smaller increase in FVII:c (P < 0.001, diet x time interaction), a greater rise in tissue plasminogen activator concentrations (P = 0.028, diet effect), and a tendency to a greater postprandial decline in PAI-1 (P = 0.06, diet effect) compared with the unsaturated test fats (O, T, and L).” “Our results indicate a lesser increase in FVIIa after the consumption of saturated fats, especially the S fat, than after unsaturated test fats.”
Randomized Controlled Trial
Prostaglandins. 1978 Apr;15(4):557-64. Prostaglandin I2 as a
potentiator of acute inflammation in rats.
Komoriya K, Ohmori H, Azuma A, Kurozumi S, Hashimoto Y, Nicolaou KC,
Barnette WE, Magolda RL. Prostaglandin I2 potentiated the paw swelling
induced by carrageenin in rats. Prostaglandin I2 (0.1 microgram) showed
similar activity to PGE1 (0.01 microgram). This potentiating property
disappeared in 60 minutes and was completely abolished by diphenhydramine (25 mg kg-1, i.p.).
In vascular permeability tests, PGI2 itself (2.5 X 10(-10) mol, 88 ng)
caused no dye leakage reaction, but PGE1 (2.5 X 10(-10) mol, 88.5 ng) caused a significant dye leakage.
This effect of PGE1 was statistically significant compared with vehicle-
or PGI2-treated groups (p less than 0.05). Prostaglandin I2
potentiated the increased vascular permeability induced by
5-hydroxytriptamine (2.5 X 10(-10)
mol), bradykinin (5 X 10(-10) mol) and histamine (2 X 10(-10) to 2 X
10(-8) mol). The potentiation was the most evident in the case of histamine.
Journal
of Lipid Research, Vol. 44, 271-279, February 2003. Arachidonic acid
and prostacyclin signaling promote adipose tissue development : a human
health concern? F.lorence Massiera*, Perla Saint-Marc*, Josiane
Seydoux , Takahiko Murata , Takuya Kobayashi , Shuh Narumiya , Philippe
Guesnet**, Ez-Zoubir Amri*, Raymond Negrel* and Gérard Ailhaud1,* Institut
de Recherche Signalisation, Biologie du Développement et Cancer, Centre
de Biochimie (UMR6543CNRS), UNSA, Faculté
des Sciences, Parc Valrose, 06108 Nice cedex 2, France Centre Médical
Universitaire, Département de Physiologie, 1 rue Michel Servet, 1211
Genève 4, Switzerland Department of Pharmacology, Kyoto University,
Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8315, Japan** Laboratoire
de Nutrition et Sécurité Alimentaire, INRA, 78352 Jouy-en-Josas, France
1 To whom correspondence should be addressed. e-mail: ailhaud@unice.fr
High fat intake is associated with fat mass gain through fatty acid
activation of peroxisome proliferator-activated receptors and
, which promote adipogenesis. We show herein that, compared to a combination
of specific agonists to both receptors or to saturated, monounsaturated,
and -3 polyunsaturated fatty acids, arachidonic acid (C20:4,
-6) promoted substantially the differentiation of clonal preadipocytes.
This effect was blocked by cyclooxygenase inhibitors and mimicked
by carbacyclin, suggesting a role for the prostacyclin receptor and
activation of the cyclic AMP-dependent pathways that regulate the expression
of the CCAAT enhancer binding proteins ß and implicated in adipogenesis.
During the pregnancy-lactation period, mother mice were fed either a
high-fat diet rich in linoleic acid, a precursor of arachidonic acid
(LO diet), or the same isocaloric diet enriched in linoleic acid and
-linolenic acid (LO/LL diet). Body weight from weaning onwards, fat
mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age
were higher with LO diet than with LO/LL diet. In contrast, prostacyclin
receptor-deficient mice fed either diet were similar in this respect,
indicating that the prostacyclin signaling contributes to adipose tissue
development. These results raise the issue of the high content of
linoleic acid of i) ingested lipids during pregnancy and lactation,
and ii) formula milk and infant foods in relation to the epidemic of
childhood obesity.
Arthritis Rheum 2000 Apr;43(4):894-900
Abnormalities of erythrocyte membrane fluidity, lipid composition, and lipid peroxidation in systemic sclerosis: evidence of free radical-mediated injury. Solans R, Motta C, Sola R, La Ville AE, Lima J, Simeon P, Montella N,
Armadans-Gil L, Fonollosa V, Vilardell M
Medicina Interna, Vall d'Hebron University General Hospital, Barcelona, Spain.
OBJECTIVE: To elucidate whether oxidative injury occurs in systemic sclerosis
(SSc) and whether it affects the erythrocyte membrane (EM) properties. METHODS:
EM fluidity and lipid composition (cholesterol:phospholipid molar ratio [C:PL],
fatty acid composition) were studied in 52 patients with SSc and in 53 subjects
without SSc (32 with primary Raynaud's phenomenon [RP] and 21 healthy subjects
[controls]). Fluidity was measured as the fluorescence anisotropy of the
hydrophobic fluorescent probe
DPH (1,6-diphenyl-1,3,5-hexatriene
peroxidation products were determined as thiobarbituric acid-reactive substances
(TBARS). RESULTS: EM fluidity was significantly lower in SSc patients than in
primary RP patients and controls (P < 0.001). The EM C:PL molar ratio was
significantly higher in SSc patients than in primary RP patients and controls (P
< 0.05). Levels of EM polyunsaturated n6 fatty acids (PUFA n6) were
significantly lower in SSc patients than in primary RP patients and controls (P
< 0.001). TBARS were significantly increased in SSc patients compared with
primary RP patients and controls (P < 0.001). Multiple regression analyses indicated that the reduced EM fluidity was partly due to its greater C:PL molar ratio, lower PUFA n6 content, and higher TBARS levels. EM fluidity was lower among patients with nailfold capillary loss (P < 0.001) and digital ischemic ulcers (P < 0.05). EM lipid peroxidation products were higher among patients with pulmonary involvement (bibasal pulmonary fibrosis [P < 0.05] and reduced levels of diffusing capacity for carbon monoxide [P < 0.001]) and among patients who were positive for anti-topoisomerase I antibodies (P < 0.05) or negative for anticentromere antibodies (P < 0.001). CONCLUSION: Our findings support the idea that oxidative injury occurs in SSc and that, through lipid peroxidation, it
induces structural and functional changes of the EM that may contribute to the
development of the microvascular
abnormalities that are seen in the disease.
Alcohol Clin Exp Res 1998 Feb;22(1):192-6
Increased circulating products of lipid peroxidation in patients with alcoholic liver disease.
Aleynik SI, Leo MA, Aleynik MK, Lieber CS
Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and
Mount Sinai School of Medicine, New York 10468, USA. F2-isoprostanes (F2-IP) and 4-hydroxynonenal (4-HNE), peroxidation products of polyunsaturated fatty acids (PUFA), are considered the most reliable indicators of endogenous lipid peroxidation in vivo. To determine to what extent these are
also altered in patients with alcoholic liver disease, plasma free and esterified F2-IP as well as 4-HNE were measured by GC/MS in 49 fasting subjects who underwent diagnostic percutaneous needle biopsies of the liver. Compared to
patients with mild steatosis and no fibrosis, free F2-IP and 4-HNE were strikingly increased in individuals with alcoholic hepatitis. There was also a significant but lesser rise of 4-HNE in patients with perivenular fibrosis. An
increase of F2-IP was also found in subjects with transition to, or complete, alcoholic cirrhosis, with a comparable trend for 4-HNE. By contrast, in patients who were drinking heavily up to 48 hr before admission, F2-IP were not abnormal,
but they increased later (p < 0.005). Contrasting with plasma free F2-IP, esterified F2-IP were not significantly changed with fibrosis. Thus, whereas
circulating esterified F2-IP were unchanged in patients with alcoholic liver disease, there was an increase in free F2-IP as well as 4-HNE during recovery from intoxication. The increase was not a result of accompanying hepatitis C but a function of the stage of alcoholic liver injury, possibly reflecting enhanced lipid peroxidation as well as interference with biliary excretion and/or hepatic esterification.
Gastroenterology.
1995 Aug;109(2):547-54. Dietary saturated fatty acids: a novel
treatment for alcoholic liver disease.
Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ
Department of Pathology, New England Deaconess Hospital, Boston, Massachusetts,
USA. BACKGROUND & AIMS: Lipid peroxidation may be important in the
pathogenesis of alcoholic liver injury. The purpose of this study was
to determine whether a saturated fatty acid-based therapy (palm oil)
could decrease lipid peroxidation and alcoholic liver injury during
ethanol withdrawal. METHODS: Three groups of male Wistar
rats (5 rats/group) were studied. Rats in group 1 were fed a fish oil-ethanol
diet for 6 weeks; rats in groups 2 and 3 were fed a fish oil-ethanol
diet for 6 weeks before treatment with fish oil-dextrose (group 2) or
palm oil-dextrose (group 3) for 2 weeks. Liver samples were analyzed
for histopathology, lipid peroxidation, fatty acid composition, cytochrome
P450 2E1 activity, and tocopherol levels. RESULTS: By 6 weeks, all rats
had developed fatty liver, inflammation, and necrosis. Group 2 showed
minimal histological improvement, whereas group 3 showed near normalization
of the histology. The improvement in group 3 was associated with decreased
lipid peroxidation and P450 2E1 activity. Higher levels of omega-3 fatty
acids were detected in group 2 than group 3. Tocopherol levels were
similar among the groups. CONCLUSIONS: A diet enriched in saturated
but not unsaturated fatty acids reversed alcoholic liver injury. This
effect may be explained by down-regulation of lipid peroxidation.Comment
in: Gastroenterology 1995 Aug;109(2):617-20
Nutrition.
2002 Jul-Aug;18(7-8):647-53. Dietary fat composition alters
pulmonary function in pigs. Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE. Department of Surgery,
The University of Texas Medical Branch, Galveston, Texas, USA. Rwolfe@utmb.edu
OBJECTIVES: We investigated the effect of various dietary fats on pulmonary
surfactant composition and lung function changes that occur before and
after endotoxin infusion in pigs. METHODS:Eighteen pigs were assigned
to three groups (n = 6 per group) to receive a diet of protein (20%
of calories), carbohydrate (20% of calories), and fat (40% of calories).
In one group the fat content consisted entirely of
palmitic acid. In the second group, fat came from
Intralipid, which provided predominantly
linoleic acid. The third group was fed fish oil. Pigs were maintained
on these diets for 21 d before the experiment. Cardiovascular and pulmonary
functions were determined on day 22. Pigs then
were infused with endotoxin (80 mg. kg(-1).
min(-1)) until the pulmonary arterial pressure reached a pressure similar
to that found in trauma victims (45 to 50 mmHg). Cardiovascular and
pulmonary function tests were then repeated, the animals killed, and
the lungs removed for study. RESULTS: Compliance was reduced
in the linoleate and fish-oil groups compared with the palmitate group
before and after endotoxin. Compliance changes in pigs fed the
linoleate and fish-oil diets were consistent with significant increases
in lung wet:dry weight ratios, increased
CO(2) retention, histologic evidence of vascular congestion, intra-alveolar
edema, and alveolar septa thickening. Changes in surfactant phosphatidylcholine
composition between groups were consistent with the notion that increased
unsaturated fatty acids could affect surfactant function. CONCLUSIONS:
We concluded that the common practice of providing calories in the form
of polyunsaturated fatty acids to critically ill patients carries the
risk of being detrimental to lung function.
Recent Dev Alcohol. 1985;3:101-22.
Synthesis
of prostaglandins and leukotrienes. Effects of ethanol. Murphy RC,
Westcott JY. Prostaglandins, thromboxane,
and leukotrienes are metabolites of arachidonic acid that have a variety
of physiological effects at low concentrations. Effects include smooth
muscle contraction, platelet aggregation, platelet disaggregation, bronchoconstriction,
increased capillary permeability, cardiac dysfunction, and polymorphonuclear
leukocyte accumulation. Although their formation does not appear
to be essential for life, these eicosanoid activities are wide ranging
and have important roles in normal physiology as well as
pathophysiology. At the center of eicosanoid biosynthesis lies the
plasma cell membrane which serves as the arachidonic acid reservoir.
It has been widely appreciated that ethanol exerts effects on the lipid
bilayer, and it is not surprising that a growing body of evidence supports
the concept that important interactions between ethanol and eicosanoid
biosynthesis can occur. Furthermore, at various steps leading to ultimate
prostaglandin, thromboxane and leukotriene production, reactive intermediates
such as radicals are involved whose lifetime in the biological milieu
can be profoundly modulated by ethanol.
J Nutr Sci
Vitaminol (Tokyo). 1984 Apr;30(2):179-85. Physiological impairment
in linoleic acid deficiency of rats and the effect of n-3 polyunsaturated
fatty acids. Iritani
N, Ikeda Y, Fukuda H. Some impairments related to membrane function
were found in linoleic acid-deficient rats and the effects of fish oil
feeding were investigated. In linoleic acid-deficient rats, glucose
transport into erythrocytes was decreased. The concentrations of plasma
free fatty acids were significantly reduced in the animals. Further, epinephrine-stimulated
lipase was remarkably less sensitive to epinephrine in the deficient
rat than in the corn oil-fed control rat.
However, these impairments were relieved by fish oil feeding. Therefore,
the impairments may be ascribed to the decrease of arachidonic acid
as a polyunsaturated fatty acid in membrane phospholipids, since n-3
polyunsaturated fatty acids appear to take the place of arachidonic
acid.
Alcohol Clin Exp Res. 2002 May;26(5):731-6. Pathogenesis of alcoholic liver disease--recent advances. Nanji AA, Su GL, Laposata M, French SW. Department of Pathology and Center for the Study of Liver Diseases, The University of Hong Kong and Queen Mary Hospital. Ananji@pathology.hku.hk The article summarizes the proceedings of a symposium on recent advances in research on the pathogenesis of alcoholic liver disease at the 2001 RSA meeting in Montreal, Canada. The chairs were Amin A. Nanji and Samuel W. French. The presentations were (1) Role of inflammatory mediators in alcoholic liver injury by Amin A. Nanji, (2) Role of endotoxin, lipopolysaccharide binding protein,
CD14 and Toll receptors in alcoholic liver injury by Grace Su, (3) Fatty acid
ethyl esters: toxicity, metabolism and markers of ethanol intake by Michael
Laposata, and (4) Cyclic changes in gene expression when rats are fed alcohol at
a
constant rate by Samuel W. French.
J Pharmacol Exp Ther. 2001 Nov;299(2):638-44. Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.
Department of Pathology and Center for the Study of Liver Diseases, The University of Hong Kong, Hong Kong, China. Ananji@pathology.hku.hk We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3
and 4 were fed fish oil and ethanol for 6 weeks before being switched to
isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid
peroxidation,
nuclear factor-kappaB (NF-kappaB) activation, and mRNAs for cyclooxygenase-2
(Cox-2) and tumor necrosis factor-alpha (TNF-alpha). Endotoxin in plasma
was determined. The most severe inflammation and fibrosis were detected
in groups 1 and 2, as were the highest levels of
endotoxin, lipid peroxidation, activation of
NF-kappaB, and mRNAs for Cox-2 and
TNF-alpha. After the rats were switched to palm oil or MCT, there
was marked histological improvement with decreased levels of endotoxin
and lipid peroxidation, absence of NF-kappaB activation, and reduced
expression of TNF-alpha and Cox-2. A diet enriched in saturated fatty
acids effectively reverses alcohol-induced necrosis, inflammation, and
fibrosis despite continued alcohol consumption. The therapeutic effects
of saturated fatty acids may be explained, at least in part, by reduced
endotoxemia and lipid peroxidation, which in turn result in decreased
activation of NF-kappaB
and reduced levels of TNF-alpha and
Cox-2.
Hepatology. 1997 Dec;26(6):1538-45.
Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis
factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat.
Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR,
Dannenberg AJ.
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard
Medical School, Boston, MA 02215, USA.
We investigated the potential of dietary saturated fatty acids to decrease
endotoxemia and suppress expression of cyclooxygenase 2 (Cox-2) and tumor
necrosis factor alpha (TNF-alpha) in established alcohol-induced liver injury.
Six groups (five rats/group) of male Wistar rats were studied. Rats in group 1
were fed a fish oil-ethanol diet for 6 weeks. Rats in groups 2, 3, and 4 were
fed fish oil and ethanol for 6 weeks. Ethanol administration was stopped at this
time, and the rats were switched to isocaloric diets containing dextrose with
fish oil (group 2), palm oil (group 3), or medium-chain triglycerides (group 4)
as the source of fat for an additional 2 weeks. Rats in groups 5 and 6 were fed
fish oil-ethanol and fish oil-dextrose, respectively, for 8 weeks. Liver samples
were analyzed for histopathology, lipid peroxidation, and levels of messenger
RNA (mRNA) for Cox-2 and TNF-alpha. Concentrations of endotoxin were determined
in plasma. The most severe inflammation and fibrosis were detected in groups 1
and 5, as were the highest levels of endotoxin, lipid peroxidation, and mRNA for
Cox-2 and TNF-alpha. After ethanol was discontinued, there was minimal
histological improvement in group 2 but near normalization of the histology,
including regression of fibrosis, in groups 3 and 4. Histological improvement
was associated with decreased levels of endotoxin, lipid peroxidation, and
reduced expression of Cox-2 and TNF-alpha. The data indicate that a diet
enriched in saturated fatty acids (groups 3 and 4) effectively reverses
alcohol-induced liver injury, including fibrosis. The therapeutic effects of
saturated fatty acids may be explained, at least in part, by reduced endotoxemia
and lipid peroxidation, which in turn result in decreased levels of TNF-alpha
and
Cox-2.
4: J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700.
Medium chain triglycerides and vitamin E reduce the severity of established
experimental alcoholic liver disease.
Nanji AA, Yang EK, Fogt F, Sadrzadeh SM, Dannenberg AJ.
Department of Pathology, New England Deaconess Hospital, Boston, Massachusetts,
USA.
Lipid peroxidation may be important in the pathogenesis of alcoholic liver
injury. We investigated the potential of medium chain triglycerides and vitamin
E to decrease lipid peroxidation and reverse established alcoholic liver i