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            Suitable Fats, Unsuitable Fats: Issues in Nutrition
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        <h1>
            Suitable Fats, Unsuitable Fats: Issues in Nutrition
        </h1>

        <p>
            For fifty years, the mass media have been making the public think about the fats in their diet, filling the
            culture with clich"s about bad saturated animal fats that raise cholesterol, or lately the trans-fats in
            margarine, and images of arteries clogged by bad fats. The public instruction about the fats we should eat
            resembles the owner's manual for a car, that tells you what kind of motor oil and fuel and coolant to use;
            they are telling us that they know how our body works, and that they know what it needs. But now, even after
            the human genome has supposedly been partly "decoded," the biological functions of the fats have hardly
            begun to be investigated.
        </p>

        <p>
            To understand the present issues regarding fats in nutrition and medicine it's helpful to look at the
            historical development of biochemical and physiological fat research in a variety of contexts, including
            agriculture and economics, as well as considering the effects of the changing ideas about cell structure,
            vitamins, hormones, immunology, brain development, evolution, and the growing understanding of the way
            physiology interacts with ecology. We need to recognize the complexity of the physiology of fats, to
            appreciate the complexity of the living organism.
        </p>
        <p>
            Financial considerations have driven fat research in very obvious ways. In 1883, Mark Twain described how
            commercial fraud was making use of new technology to substitute cheap fats and oils for butter and olive
            oil.. Hard fats such as tallow, which had been used for making soap and candles, began to be widely used as
            a substitute for butter in the 19th century. Around 1912, chemists found economical ways to solidify (for
            use as a butter substitute) the very cheap liquid oils, such as cottonseed oil, linseed oil, whale oil, and
            fish oils, which been used mostly as fuels or varnish. The seed oils were so cheap that meat packers quickly
            became major producers of hydrogenated cottonseed and soy oils, to extend their limited supply of lard or
            tallow for sale as shortening or margarine.
        </p>
        <p>
            Between 1912 and 1927 there were several studies that reported that animals could live on a fat-free diet,
            and that in fact they lived longer, and without the normal mortality from cancer. In the 1940s and 1950s,
            most textbooks that mentioned the idea that certain fats were essential nutrients described it as a
            controversial idea. But the oil industries used public relations effectively to sell the medical (heart
            protective) benefits of a diet containing increased amounts of linoleic and linolenic acids, which they
            called the essential fatty acids. They began citing a 1929 publication (by G. Burr and M. Burr) that claimed
            to demonstrate the essentiality of those fatty acids, while ignoring the publications that pointed in
            different directions.
        </p>
        <p>
            The cheapness of the seed oils led to their use in animal feeds, to promote growth. By the 1940s, the
            polyunsaturated oils, including fish oils, were known to cause deterioration of the brain, muscles, and
            gonads in a variety of animals, and this was found to be caused mainly by their destruction of vitamin E. A
            little later, the disease called steatitis or yellow fat disease was found to be produced in various animals
            that were fed too much fish or fish oil.
        </p>
        <p>
            The reason linseed oil and fish oil were used for making varnishes and paints was that they are "drying
            oils," reacting with oxygen to polymerize and harden. The physical and chemical propertiess of the oils are
            fairly well understood, and among the polyunsaturated fatty acids (PUFA) the omega -3 fatty acids react most
            easily with oxygen. Heat, light, and moisture increase their spontaneous interactions with oxygen, and
            besides polymerizing, these oils produce a variety of reactive particles, including acrolein, which combine
            with other substances, such as cellular proteins and DNA, with highly toxic effects. At low temperatures and
            low oxygen concentrations these oils are not highly reactive. Fats that harden at low temperatures (as
            saturated fats do) wouldn't be convenient for organisms that live in a cool environment, and so organisms
            regulate the type of fat they synthesize according to the temperature of their tissues. The fact that
            certain types of polyunsaturated fatty acids function nicely in fish, worms, and insects, doesn't mean that
            they are ideal fats for mammals.
        </p>

        <p>
            The fact that vitamin E prevented or cured some of the major diseases in farm animals caused by excessive
            PUFA, and that it could retard the development of rancidity in stored oils, led quickly to the persistent
            belief that lipid peroxidation is the only toxic effect of the vegetable oils. However, the oils were being
            seen to cause other problems, including accelerated aging and obesity, but those problems weren't of
            interest to farmers, who wanted to sell plump young animals as cheaply and quickly as possible. Even fresh
            oils have toxic effects, and the oxidative damage they do is often the consequence of these other toxic
            actions.
        </p>
        <p>
            Another cheap food additive, coconut oil, was found to increase feed consumption while slowing weight gain,
            so it wasn't popular in the meat industry. The highly unsaturated seed oils had the opposite effect, of
            producing a rapid fattening of the animal, while decreasing feed consumption, so by 1950 corn and soybeans
            were widely considered to be optimal feeds for maximizing profits in the production of meat animals. It was
            at this time that the industry found that it could market the liquid oils directly to consumers, as
            health-promoting foods, without bothering to turn them into solid shortening or margarine. Somehow, few
            physiologists continued to think about the implications of metabolic slowing, obesity, and the related
            degenerative diseases.
        </p>
        <p>
            As vitamin research advanced in the 1940s, Roger Williams' lab at the Clayton Foundation Biochemical
            Institute, University of Texas at Austin, recognized the "fat deficiency disease" of the Burrs as a
            deficiency of vitamin B6, and showed that when they produced the condition with a diet similar to the one
            the Burrs had used, they could cure it by administering vitamin B6. In the early 1930s George Burr had
            discovered that animals on a fat free diet had an extremely high rate of metabolism, but he didn't
            investigate the important ramifications of that observation, such as their increased need for vitamins and
            minerals, in accordance with their rate of metabolism. The PUFA slowed metabolism, and that effect was good
            for agriculture.
        </p>

        <p>
            The commercial pressure on fat research has created a new way of writing research reports, that several
            decades earlier wouldn't have been acceptable. For example, the effects of a specific fat on a few of the
            components of a complex process such as clotting are often described in the title, introduction, and
            conclusion of an article as if they were revealing a way to prevent heart disease. The effects of
            unsaturated fats on cells <em>
                in vitro</em> are often the opposite of their effects in living animals, but editors are allowing
            authors to claim that their <em>in vitro</em>
            results justify dietary or therapeutic use of the fats. Journals of medicine and nutrition are now preferred
            sites for commercial press releases, composed to superficially resemble scientific reports.
        </p>
        <p>
            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.
        </p>

        <p>
            Ordinarily, in biochemistry and physiology the inhibition of an enzyme is taken as a suggestion of toxicity,
            but when the point of reference is the idea of the goodness of PUFA, the <em>activity</em> of an intrinsic
            enzyme is taken to be evidence of harm, and its <em>inhibition</em> (by PUFA) is taken to be the proper,
            healthful situation. The enzyme that produces the Mead fatty acid is strongly inhibited by PUFA seed oils
            (less strongly by fish oils), and so the presence of the Mead acid in the tissues is taken as evidence that
            the animal is suffering damage resulting from the absence of PUFA. The Mead acid happens to have some
            valuable anti-inflammatory effects, and is associated with many biological advantages, but research in that
            direction is prevented by the lack of funding.
        </p>
        <p>
            By 1920, the polyunsaturated fatty acids were recognized to inhibit proteolytic enzymes. At that time, the
            production of unsaturated fat was considered to be a feature of certain pathogens, able to overcome the
            proteolytic-phagocytic functions of the immune system.
        </p>
        <p>
            Scattered studies have found that polyunsaturated fats inhibit the proteolytic enzymes involved in the
            digestion of food, in the removal of clots, in the formation of thyroid hormone, and many other essential
            physiological processes. But currently, the only implication being drawn from this broad class of effects of
            the PUFA is that some proteolytic enzymes are involved in disease processes, and consequently increased
            consumption of PUFA would be appropriate, because of their ability to suppress a conditionally harmful
            proteolytic enzyme. Since the organism consists mainly of proteins, there are complex innate systems for
            regulating the proteolytic enzymes, activating or inactivating them as needed, and such complexity isn't
            likely to depend on variable, unstable dietary factors. Exogenous substances that inhibit some proteases
            could create an unlimited variety of functional and anatomical irregularities.
        </p>
        <p>
            Some of the interesting enzymes affected specifically by polyunsaturated fatty acids are those involved in
            hormone production. While they inhibit the formation of progesterone and androgens, they activate the
            synthesis of estrogen, which in turn activates the release of more free polyunsaturated fatty acids from the
            tissues, in a positive feedback pattern.
        </p>

        <p>
            The inhibition of detoxification enzymes by PUFA (Tsoutsikos, et al., 2004) affects many processes, such as
            the elimination of estrogen, contributing to the positive feedback between estrogen and the oils. The
            meaning of this tends to be lost, because of the estrogen industry's effective campaigns.
        </p>
        <p>
            Another situation in which fatty acids participate in a positive feedback system is the stress reaction, in
            which the released fatty acids impair mitochondrial energy production, increasing the stress and leading to
            further release of fatty acids.
        </p>
        <p>
            One of the perennial theories of aging that has remained viable is the metaplasm/lipofuscin/age pigment
            theory, the idea that a toxic material accumulates in tissues over time. The age pigment contains proteins,
            cross-linked PUFA, and metals. The inhibition of proteolytic enzymes is involved in its accumulation, and
            the ratio of PUFA to saturated fatty acids is an important factor in its formation. Estrogen is one of the
            factors that can promote the formation of age pigment, probably partly because its lipolytic action
            increases the cells' exposure to free fatty acids. The lipofuscin contributes to inhibition of proteolysis,
            probably partly through increased production of free radicals and hydrogen peroxide.
        </p>
        <p>
            The proteolytic enzymes are an essential part of innate immunity, and the highly unsaturated fatty acid,
            EPA, which is the most immunosuppressive of the fats, strongly inhibits proteolysis in some cells. The
            natural killer (NK) cells and phagocytic cells are two types of cell that are suppressed by PUFA, and they
            are involved in many kinds of physiological events, not just the killing of tumor cells and virus infected
            cells.
        </p>
        <p>
            The immunosuppressive effects of PUFA are very general. Many metabolites that are known to have harmful
            effects on the immune system are increased by the PUFA (histamine [Masini, et al., 1990], serotonin,
            lactate, nitric oxide [Omura, et al., 2001]). These substances are also involved in tumor development.
        </p>

        <p>
            Besides inhibiting enzymes and being converted into prostaglandins, the polyunsaturated fatty acids have
            direct effects, as signals (or interference with signals) on many tissues. The belief that the PUFA are
            essential nutrients has influenced the way cellular excitability thresholds are being interpreted. Anxiety
            and panic may be interpreted as alertness, calmness may be interpreted as stupidity. Specifically, long-term
            potentiation (LTP) may contribute to seizures, senility, and excitotoxicity, as well as to learning, but
            many titles and conclusions equate increased LTP with "improved LTP," implying that it has biological value
            to the animal.
        </p>
        <p>
            The ability of nerve cells to become quiescent after excitation is essential to learning and perception.
            This ability is lost with aging, as the functional balance in the brain shifts away from GABA-ergic to
            glutamatergic nerves. The polyunsaturated fatty acids promote the excitatory nervous state. The combination
            of respiratory inhibition with excitation can produce excitotoxic cell death. If the doctrine of
            "essentiality of PUFA" hadn't been so influential, different interpretations of excitatory thresholds,
            energy metabolism, and even cell structure would have been allowed to develop more fully.
        </p>
        <p>
            The concentration of polyunsaturated fats in the brain has led many people to say that the "nutritionally
            essential fatty acids," especially the omega -3 fatty acids, are essential for brain development (for the
            formation of nerve cell membranes), and for the formation of synapses, and that increasing the amount of
            those fats in the diet would be desirable. The types of argument they use simply ignore the real
            evidence<strong>:</strong>

            Cells can multiply indefinitely in culture dishes without the essential fatty acids, insects can multiply
            for generations on diets without the unsaturated fats, forming normal synapses and brains, and mammals fed
            diets with extremely small amounts of the unsaturated fats grow with perfectly normal--possibly
            superior--brains.
        </p>
        <p>
            One of the fats in the omega -9 series, that the human body can synthesize, nervonic acid, is a major
            constituent of brain tissue, but its important functions in brain development have hardly been investigated.
            Unlike the unsaturated fatty acids oleic acid, linoleic acid, and eicosapentaenoic acid (EPA), nervonic acid
            isn't associated with the "coronary risk factors," and it has been suggested that it might be used in adults
            to prevent obesity-related diseases. (Oda, et al., 2005).
        </p>
        <p>
            One major area of research that has been neglected involves the role of fats in modifying the ways in which
            proteins and nucleic acids interact with water--arguably the most basic of all physiological processes.
            Unsaturated fats are more water soluble than saturated fats, and they are involved in many problems of
            permeability and edema.
        </p>
        <p>
            In aging and evolution, there are systematic changes in tissue water content that appear to correspond to
            changes in rate of metabolism, to the degree of unsaturation of cellular fats, and to thyroid function and
            temperature. Metabolic intensity and longevity can be modified by changing the degree of saturation of fats
            in the diet and tissues, but--despite almost a century of sporadic investigations--no one has yet worked out
            in detail the most appropriate way to do this. But it has become clear that the "uncoupled" mitochondrion,
            that "wastes oxygen and calories," is protective against free radicals, cancer, and aging. Thyroid hormone
            and the absence of PUFA are important factors in supporting the "wasteful" mitochondrion.
        </p>
        <p>
            Although the complex interactions of anatomy, energy, temperature, fat nutrition, tissue water content, and
            hormones haven't been systematically investigated, some of the principles regarding the biological
            suitability of specific fats are already being applied in the limited context of therapy.
        </p>
        <p>
            At present, the most important issue is to recognize the dangers presented by the intrusion of corporate
            power into science, especially as it relates to nutrition and medicine, and to consider the implications of
            the known effects of the PUFA on all of our biological systems.
        </p>
        <p>
            The food-derived polyunsaturated fatty acids play important roles in the development of all of the problems
            associated with aging--reduced immunity, insomnia, decreased learning ability, substitution of fat for
            muscle, susceptibility to tissue peroxidation and inflammation, growth of tumors, etc., and are probably
            involved in most other health problems, even in children. If research hadn't been guided by the economic
            interests of the seed oil industry, many of those problems would have been solved by now.
        </p>
        <p>
            The influence of the mass media on science can be seen in two issues that are currently well known.
        </p>

        <p>
            A popular test used for evaluating diabetes is the measurement of glycated hemoglobin, the attachment of a
            sugar-like fragment to the protein of hemoglobin. This is used to judge whether blood sugar is being
            controlled adequately. The glycation of proteins is widely believed to be a central process in aging, and is
            often used to argue that people should reduce their sugar consumption.
        </p>
        <p>
            Another well publicized problem supposedly involving the reaction between sugars and proteins has to do with
            the discovery of the carcinogen, acrylamide, in breads and french fries. The Whole Foods Market was sued in
            California for selling whole wheat bread without a warning that it contained a carcinogen.
        </p>
        <p>
            But the changes in proteins that occur in diabetes are mainly produced by the breakdown products of
            polyunsaturated fatty acids. Acrylamide is produced largely by the reaction of PUFA with proteins.
        </p>
        <p>
            Sugar, by reducing the level of free fatty acids in the body, actually tends to protect against these toxic
            effects of the PUFA. Diabetes, like cancer, has been known for a long time to be promoted by unsaturated
            oils in the diet, rather than by sugar. The seed oil industry has been more effective than the sugar
            industry in lobbying and advertising, and the effects can be seen in the assumptions that shape medical and
            biological research.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            Biochem Pharmacol. 1990 Mar 1;39(5):879-89. <strong>Histamine release from rat mast cells induced by
                metabolic activation of polyunsaturated fatty acids into free radicals.</strong> Masini E, Palmerani B,
            Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.
        </p>

        <p>
            Int Heart J. 2005 Nov;46(6):975-85. <strong>Relationships between serum unsaturated fatty acids and coronary
                risk factors: negative relations between nervonic acid and obesity-related risk factors.</strong> Oda E,
            Hatada K, Kimura J, Aizawa Y, Thanikachalam PV, Watanabe K. "The objective of the present study was to
            analyze the relationships between serum USFA and CRF [coronary risk factors]." "<strong><hr /></strong>"
        </p>
        <p>
            FEBS Lett. 2001 Jan 5;487(3):361-6. <strong>Eicosapentaenoic acid (EPA) induces Ca(2+)-independent
                activation and translocation of endothelial nitric oxide synthase and endothelium-dependent
                vasorelaxation.</strong> Omura M, Kobayashi S, Mizukami Y, Mogami K, Todoroki-Ikeda N, Miyake T,
            Matsuzaki M. "EPA stimulated NO production even in endothelial cells in situ loaded with a cytosolic Ca(2+)
            chelator . . . which abolished the [Ca(2+)]i elevations induced by ATP and EPA."
        </p>

        <p>
            Biochem Pharmacol. 2004 Jan 1;67(1):191-9. <strong>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.</strong> Tsoutsikos P, Miners JO, Stapleton A, Thomas A,
            Sallustio BC, Knights KM.
        </p>
        <p>
            Lipids. 1997 Dec;32(12):1265-70. <strong>Dietary fatty acid profile affects endurance in rats.</strong> Ayre
            KJ, Hulbert AJ. "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 &lt;
            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 &lt; 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."
        </p>

        <p>
            Ann Biol Clin (Paris) 2000 Sep-Oct;58(5):595-600.<strong> [Studies on the genotoxic</strong>
            <strong>
                effects of crude liver oils from 3 species of Mediterranean sharks by means of in vitro micronucleus
                test using human lymphocytes]
            </strong>
            Bartfai E, Orsiere T, Duffaud F, Villani P, Pompili J, Botta A. "The results of this experimental study show
            that the crude liver oils of three species of sharks are genotoxic and confirm a high carcinogenic risk."
        </p>
        <p>
            Vaccine. 2002 Jan 31;20(9-10):1435-44. <strong>Long-term influence of lipid nutrition on the induction of
                CD8(+) responses to viral or bacterial antigens.</strong>
            Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ.
        </p>

        <p>
            J Nutr. 2001 Sep;131(9):2370-7.<strong>
                Dietary conjugated linoleic acid modulates phenotype and effector functions of porcine CD8(+)
                lymphocytes.</strong>
            Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ.
        </p>
        <p>
            J Anim Sci, 1984 Apr, 58:4, 971-8. <strong>Essential fatty acid status and characteristics associated with
                colostrum-deprived gnotobiotic and conventional lambs. Growth, organ development, cell membrane
                integrity and factors associated with lower bowel function.</strong> Bruckner G; Grunewald KK; Tucker
            RE; Mitchell GE Jr "The absence of dietary linoleic acid decreased liver and spleen weights and, in general,
            suppressed development of organs except the brain." "The results indicate that neonatal colostrum-deprived
            lambs have an EFA requirement, as evidenced by decreased growth and performance characteristics in the GN
            linoleic deficient vs GN supplemented group, and suggests that the required level is in excess of .32% of
            the total caloric intake as linoleic acid."
        </p>
        <p>
            Crit Care Med. 1996 Jul;24(7):1129-36. <strong>An increase in serum C18 unsaturated free fatty acids as a
                predictor of the development of acute respiratory distress syndrome.
            </strong>Bursten SL, Federighi DA, Parsons P, Harris WE, Abraham E, Moore EE Jr, Moore FA, Bianco JA, Singer
            JW, Repine JE.
        </p>

        <p>
            Free Radic Biol Med. 1999 Jul;27(1-2):51-9. <strong>Arachidonic acid interaction with the mitochondrial
                electron transport chain promotes reactive oxygen species generation.</strong> Cocco T, Di Paola M, Papa
            S, Lorusso M. "It is shown that arachidonic acid causes an uncoupling effect under state 4 respiration of
            intact mitochondria as well as a marked inhibition of uncoupled respiration. While, under our conditions,
            the uncoupling effect is independent of the fatty acid species considered, the inhibition is stronger for
            unsaturated acids. Experiments carried out with mitochondrial particles indicated that the arachidonic acid
            dependent decrease of the respiratory activity is caused by a selective inhibition of Complex I and III. It
            is also shown that arachidonic acid causes a remarkable increase of hydrogen peroxide production when added
            to mitochondria respiring with either pyruvate+malate or succinate as substrate."
        </p>
        <p>
            Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):256-68. <strong>Lipid peroxidation in diabetes mellitus.</strong>
            Davi G, Falco A, Patrono C.
        </p>
        <p>
            Naunyn Schmiedebergs Arch Pharmacol. 2005 Mar;371(3):202-11. Epub 2005 Apr 15. <strong>Antiarrhythmic and
                electrophysiological effects of long-chain omega-3 polyunsaturated fatty acids.
            </strong>
            Dhein S, Michaelis B, Mohr FW. "<strong>Atrioventricular conduction time was slowed only by DHA and
                EPA."</strong> "Regarding antiarrhythmic activity we found that the <strong>threshold for elicitation of
                a ventricular extrasystole was concentration-dependently enhanced by DHA and EPA, but not by ALA. DHA
                dose-dependently reduced longitudinal propagation velocity V(L)</strong>

            and to a lower extent transverse velocity V(T)."
        </p>
        <p>
            J Biol Chem. 2002 Oct 18;277(42):39368-78. <strong>The mechanism of docosahexaenoic acid-induced
                phospholipase D activation inhuman lymphocytes involves exclusion of the enzyme from lipid
                rafts.</strong> Diaz O, Berquand A, Dubois M, Di Agostino S, Sette C, Bourgoin S, Lagarde M, Nemoz G,
            Prigent AF. "Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid that inhibits T lymphocyte
            activation, has been shown to stimulate phospholipase D (PLD) activity in stimulated human peripheral blood
            mononuclear cells (PBMC)." "<strong>This PLD activation might be responsible for the immunosuppressive
                effect of DHA because it is known to transmit antiproliferative signals in lymphoid cells."</strong>
        </p>
        <p>
            Nutrition. 2003 Feb;19(2):144-9. <strong>
                Diets rich in polyunsaturated fatty acids: effect on hepatic metabolism in rats.</strong> Gaiva MH,
            Couto RC, Oyama LM, Couto GE, Silveira VL, Ribeiro EB, Nascimento CM. "Male Wistar rats, just weaned, were
            fed ad libitum for 8 wk with one of the following diets: rat chow (C), rat chow containing 15% (w/w) soybean
            oil (S), rat chow containing 15% (w/w) fish oil (F), and rat chow containing 15% soy bean and fish oil (SF;
            5:1, w/w)." "Body weight gain was higher in F and SF than in C and S rats. Liver weight, lipid content, and
            lipogenesis rate increased in F and SF rats, although adenosine triphosphate citrate lyase activity
            decreased. Glycogen concentration decreased in S, F, and SF rats compared with C rats."
        </p>
        <p>
            Br J Nutr. 2001 Sep;86(3):371-7. <strong>Polyunsaturated fatty acid-rich diets: effect on adipose tissue
                metabolism in rats.</strong> Gaiva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Riberio EB, Nascimento
            CM. "Wistar rats were fed ad libitum, for 8 weeks with one of the following diets: C, rat chow; S, rat chow
            containing 15 % (w/w) soyabean oil; F, rat chow containing 15 % (w/w) fish oil; SF, rat chow containing 15 %
            (w/w) soyabean and fish oil (5:1, w/w)." "Energy intake was reduced while carcass lipid content was
            increased in the three fat-fed groups." "These results indicate that enrichment of the diet with
            polyunsaturated fatty acids causes changes in adipose tissue metabolism that favour fat deposition.
            Different metabolic pathways were preferentially affected by each type of fatty acid used."
        </p>
        <p>
            Adv Exp Med Biol 266:3-15, 1989, <strong>"Lipofuscin and ceroid formation: the cellular recycling
                system,"</strong> Harman, D.
        </p>
        <p>
            Mech Ageing Dev 2001 Apr 15;122(4):427-43. <strong>Effect of the degree of fatty acid unsaturation of rat
                heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage.</strong>
            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."
        </p>

        <p>
            Biochem J. 1994 May 15;300 ( Pt 1):251-5. <strong>Regulation of fibrinolysis by non-esterified fatty
                acids.</strong> 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."
        </p>
        <p>
            B. A. Houssay and C. Martinez, <strong>"Experimental diabetes and diet,"</strong>
            Science 105, 548-549, 1947.
        </p>
        <p>
            J Theor Biol. 2005 May 21;234(2):277-88. <strong>On the importance of fatty acid composition of membranes
                for aging.</strong> Hulbert AJ.
        </p>

        <p>
            Mech Ageing Dev. 2006 Apr 16; <strong>Extended longevity of wild-derived mice is associated with
                peroxidation-resistant membranes.
            </strong>
            Hulbert AJ, Faulks SC, Harper JM, Miller RA, Buffenstein R. "Muscle and liver phospholipids from these
            long-living mice lines have a reduced amount of the highly polyunsaturated omega-3 docosahexaenoic acid
            compared to the DC mice, and consequently their membranes are less likely to peroxidative damage. The
            relationship between maximum longevity and membrane peroxidation index is similar for these mice lines as
            previously observed for mammals in general. It is suggested that peroxidation-resistant membranes may be an
            important component of extended longevity."
        </p>
        <p>
            Virchows Arch B Cell Pathol. 1975 Nov 21;19(3):239-54.<strong>
                [Ultrastructure and morphogenesis of ceroid pigment. II. Late changes of lysosomes in Kupffer cells of
                rat liver after phagocytosis of unsaturated lipids]
            </strong>
            Kajihara H, Totovic V, Gedigk P. "These lipids, which have been changed in their molecular structure, cannot
            be hydrolized by lysosomal enzymes. They remain as an indigestible material, as a waste product in lysosomal
            residual bodies. Both lipofuscin and ceroid are lysosomal structures containing oxidized and polymerized
            lipids."
        </p>
        <p>
            Reprod Nutr Dev. 1998 Jan-Feb;38(1):31-7. <strong>Effect of a high linoleic acid diet on delta 9-desaturase
                activity, lipogenesis and lipid composition of pig subcutaneous adipose tissue.</strong> Kouba M, Mourot
            J.
        </p>

        <p>
            Gerontology 1993;39(1):7-18.<strong>
                Modulation of membrane phospholipid fatty acid composition by age and food restriction.</strong>
            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."
        </p>
        <p>
            Free Radic Biol Med 1999 Feb;26(3-4):260-5. <strong>Modulation of cardiac mitochondrial membrane fluidity by
                age and calorie intake.</strong> 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."
        </p>

        <p>
            Lipids 2001 Jun;36(6):589-93. <strong>Effect of dietary restriction on age-related increase of liver
                susceptibility to peroxidation in rats.</strong> Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.
        </p>
        <p>
            Lipids 22(3), 133-6, 1987. <strong>Effects of parenteral nutrition with high doses of linoleate on the
                developing human liver and brain,</strong> Martinez, M., and A. Ballabriga.
        </p>
        <p>
            J Pharmacol Exp Ther. 1995 Jan;272(1):469-75. <strong>Acetic acid-induced colitis in normal and essential
                fatty acid deficient rats.</strong> Mascolo N, Izzo AA, Autore G, Maiello FM, Di Carlo G, Capasso F.
        </p>

        <p>
            Biochem Pharmacol. 1990 Mar 1;39(5):879-89. <strong>Histamine release from rat mast cells induced by
                metabolic activation of polyunsaturated fatty acids into free radicals.</strong> Masini E, Palmerani B,
            Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.
        </p>
        <p>
            J Nutrit 10:63(1935). <strong>The effect of retarded growth upon length of the life span and upon the
                ultimate body size.</strong> McCay, CM., Crowell, MF., and Maynard, LA.
        </p>
        <p>
            McCollum EV. 1957. <strong>A History of Nutrition.</strong> Boston: Houghton Mifflin. p 374.
        </p>

        <p>
            J Biol Chem. 2003 Oct 24;278(43):42012-9. <strong>Pyridoxamine traps intermediates in lipid peroxidation
                reactions in vivo: evidence on the role of lipids in chemical modification of protein and development of
                diabetic complications.</strong>
            Metz TO, Alderson NL, Chachich ME, Thorpe SR, Baynes JW.
        </p>
        <p>
            FEBS Lett. 1998 Oct 16;437(1-2):24-8. <strong>Generation of protein carbonyls by glycoxidation and
                lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids.
            </strong>
            Miyata T, Inagi R, Asahi K, Yamada Y, Horie K, Sakai H, Uchida K, Kurokawa K.
        </p>
        <p>
            Naunyn Schmiedebergs Arch Pharmacol. 1996 Jul;354(2):109-19. <strong>Exposure to the n-3 polyunsaturated
                fatty acid docosahexaenoic acid impairs alpha 1-adrenoceptor-mediated contractile responses and inositol
                phosphate formation in rat cardiomyocytes.</strong> Reithmann C, Scheininger C, Bulgan T, Werdan K. "The
            results presented show that <strong>chronic n-3 polyunsaturated fatty acid pretreatment of rat
                cardiomyocytes leads to a marked impairment of alpha 1-adrenoceptor-induced positive inotropic effects
                and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation."
            </strong>
        </p>

        <p>
            Nutrition. 2000 Jan;16(1):11-4<strong>. Effects of eicosapentaenoic acid intake on plasma fibrinolytic and
                coagulation activity by using physical load in the young.</strong> Sakamoto N, Nishiike T, Iguchi H,
            Sakamoto K. "<strong>Thus, as determined by the load, a small amount of daily EPA intake clearly decreased
                fibrinolytic activity and increased coagulation activity."</strong>
        </p>
        <p>
            Diabetes. 2005 Aug;54(8):2314-9. <strong>Insulin resistance and type 2 diabetes in high-fat-fed mice are
                linked to high glycotoxin intake.</strong> Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H.
            "These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged
            high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets."
        </p>
        <p>
            Nutr Cancer 1998;30(2):137-43. <strong>Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on
                mammary carcinogenesis in rats.</strong> Sasaki T, Kobayashi Y, Shimizu J, Wada M, In'nami S, Kanke Y,
            Takita T. "Dietary fat was fed to the rats as 10% of the total feed weight, starting two weeks before the
            initiation. 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. <strong>As the n-3/n-6 ratios
                were elevated, the total number and weight of tumors increased gradually."</strong> "These results
            suggested that the increase in the n-3/n-6 ratio of dietary fat with the fixed PUFA-to-saturated fatty acid
            ratio cannot suppress the mammary carcinogenesis but can promote development of tumors, despite reduced PGE2
            concentration in the tumor."
        </p>

        <p>
            J Cardiovasc Pharmacol. 2006 Mar;47(3):493-9. <strong>Mildronate, a novel fatty acid oxidation inhibitor and
                antianginal agent, reduces myocardial infarct size without affecting hemodynamics.</strong> Sesti C,
            Simkhovich BZ, Kalvinsh I, Kloner RA. "Mildronate is a fatty acid oxidation inhibitor approved as an
            antianginal drug in parts of Europe."
        </p>
        <p>
            J Nutr 2000 Dec;130(12):3028-33. <strong>Polyunsaturated (n-3) fatty acids susceptible to peroxidation are
                increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils.</strong> Song
            JH, Fujimoto K, Miyazawa T.. "Thus, high incorporation of (n-3) fatty acids (mainly DHA) into plasma and
            tissue lipids due to DHA-containing oil ingestion may undesirably affect tissues by enhancing susceptibility
            of membranes to lipid peroxidation and by disrupting the antioxidant system."
        </p>
        <p>
            Diabetes Nutr Metab. 2002 Aug;15(4):205-14. <strong>Long-term effect of fish oil diet on basal and
                stimulated plasma glucose and insulin levels in ob/ob mice.</strong>

            Steerenberg PA, Beekhof PK, Feskens EJ, Lips CJ, Hoppener JW, Beems RB. "We have investigated, in comparison
            to low and high fat diets, the effect of a fish oil diet on basal and stimulated plasma glucose and insulin
            levels in male and female ob/ob mice." "Intercurrent deaths were found especially in the fish oil diet
            group. Compared to the other diet groups, plasma insulin levels of the fish oil diet group were
            significantly increased 3 months after the start of the diet and remained higher for another 3 months." "At
            12 months, microscopy revealed an increased severity of hepatic brown pigment accumulation and
            extramedullary haematopoiesis in the spleen of mice fed with fish oil." "Fish oil diet also increased
            intercurrent mortality. However, a consistent course of death could not be established using morphological
            parameters."
        </p>
        <p>
            J Biol Chem. 2002 Feb 15;277(7):5692-7. <strong>Unsaturated fatty acids inhibit cholesterol efflux from
                macrophages by increasing degradation of ATP-binding cassette transporter A1.</strong> Wang Y, Oram JF.
            "These findings raise the possibility that an increased supply of unsaturated fatty acids in the artery wall
            promotes atherogenesis by impairing the ABCA1 cholesterol secretory pathway in macrophages."
        </p>
        <p>
            J Biol Chem. 2005 Oct 28;280(43):35896-903. Epub 2005 Aug 23. <strong>Unsaturated fatty acids phosphorylate
                and destabilize ABCA1 through a phospholipase D2 pathway.</strong> Wang Y, Oram JF. "ATP-binding
            cassette transporter ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL
            apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are elevated
            in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein." "Unsaturated but
            not saturated fatty acids stimulated phospholipase D (PLD) activity, the PLD inhibitor 1-butanol prevented
            the unsaturated fatty acid-induced reduction in ABCA1 levels, and the PLD2 activator mastoparan markedly
            reduced ABCA1 protein levels, implicating a role for PLD2 in the ABCA1 destabilizing effects of fatty
            acids." "These data provide evidence that intracellular unsaturated acyl-CoA derivatives destabilize ABCA1
            by activating a PLD2 signaling pathway."
        </p>

        <p>
            Isr J Med Sci. 1996 Nov;32(11):1134-43. <strong>Diet and disease--the Israeli paradox: possible dangers of a
                high omega-6 polyunsaturated fatty acid diet.</strong> Yam D, Eliraz A, Berry EM. "Thus, rather than
            being beneficial, high omega-6 PUFA diets may have some long-term side effects, within the cluster of
            hyperinsulinemia, atherosclerosis and tumorigenesis."
        </p>

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