Title: Omega 3 – Omega 6: What is right for the liver?
Abstract: Linoleic and α-linolenic acids are the fatty acids designated as "essential" since they are not synthesized by mammalian cells and must be provided in the diet. The recent dietary shift towards the consumption of n-6 (omega-6) at the expense of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) is thought to be a primary cause of many diseases related to the Western diet. The body converts linoleic acid to arachidonic acid and derives eicosapentaenoic acid from α-linolenic acid. Ideally the effects of these fatty acids and their eicosanoid derivatives are tailored to the specific biological needs of the body. The balance between n-3 and n-6 PUFAs is essential for metabolism and maintenance of the functions of both classes. The availability of n-3 long chain PUFAs plays a major role in regulating both fat accumulation and its elimination by the liver. Derangement of hepatic n-6:n-3 PUFA ratio impacts on the histological pattern of fatty liver through modulation of the amount of intrahepatic lipids. Moreover, the influence of PUFAs and their eicosanoid products on hepatic microcirculation and ischemia/reperfusion injury has been demonstrated in many studies. This concise review article will focus on the role of PUFAs and eicosanoids in hepatic steatosis, microcirculation and ischemia/reperfusion injury. Linoleic and α-linolenic acids are the fatty acids designated as "essential" since they are not synthesized by mammalian cells and must be provided in the diet. The recent dietary shift towards the consumption of n-6 (omega-6) at the expense of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) is thought to be a primary cause of many diseases related to the Western diet. The body converts linoleic acid to arachidonic acid and derives eicosapentaenoic acid from α-linolenic acid. Ideally the effects of these fatty acids and their eicosanoid derivatives are tailored to the specific biological needs of the body. The balance between n-3 and n-6 PUFAs is essential for metabolism and maintenance of the functions of both classes. The availability of n-3 long chain PUFAs plays a major role in regulating both fat accumulation and its elimination by the liver. Derangement of hepatic n-6:n-3 PUFA ratio impacts on the histological pattern of fatty liver through modulation of the amount of intrahepatic lipids. Moreover, the influence of PUFAs and their eicosanoid products on hepatic microcirculation and ischemia/reperfusion injury has been demonstrated in many studies. This concise review article will focus on the role of PUFAs and eicosanoids in hepatic steatosis, microcirculation and ischemia/reperfusion injury. Fat is increasingly recognized as a central feature of many biological processes. Dietary fat may influence a variety of physiological events in the human body and thereby could impact on the pathogenesis of various diseases [[1]Lee S. Gura K.M. Puder M. Omega-3 fatty acids and liver disease.Hepatology. 2007; 45: 841-845Crossref PubMed Scopus (62) Google Scholar]. Properties of fat are influenced by fatty acid components. Fatty acids are categorized into either saturated or unsaturated, respectively, depending on absence or presence of a carbon-to-carbon double bond. Unsaturated fatty acids are further divided into 2 subgroups: monounsaturated fatty acids containing only one double bond and polyunsaturated fatty acids (PUFAs) which harbor two or more double bonds [[2]Bezard J. Blond J.P. Bernard A. Clouet P. The metabolism and availability of essential fatty acids in animal and human tissues.Reprod Nutr Dev. 1994; 34: 539-568Crossref PubMed Scopus (194) Google Scholar]. Common monounsaturated fatty acids include palmitoleic and oleic acids. PUFAs are classified according to the original fatty acids from which they are synthesized into two distinct families, namely n-6 (omega-6) PUFAs, which derive from linoleic acid and n-3 (omega-3) PUFAs, which come from α-linolenic acid (Table 1) [[3]Stulnig T.M. Immunomodulation by polyunsaturated fatty acids: mechanisms and effects.Int Arch Allergy Immunol. 2003; 132: 310-321Crossref PubMed Scopus (165) Google Scholar]. Contrary to other fatty acids, linoleic and α-linolenic acids cannot be synthesized de novo by mammalian cells; therefore they are termed "essential" and must be obtained in adequate amounts from diet. The main sources of linoleic acid include cereals, eggs, animal fat, whole-grain breads and sunflower and corn oils. α-Linolenic acid is present in abundant amounts in leafy green vegetables, walnuts and canola, flaxseed and rapeseed oils. Marine foods represent good sources for the n-3 long chain PUFAs such as eicosapentaenoic and docosahexaenoic acids [2Bezard J. Blond J.P. Bernard A. Clouet P. The metabolism and availability of essential fatty acids in animal and human tissues.Reprod Nutr Dev. 1994; 34: 539-568Crossref PubMed Scopus (194) Google Scholar, 4Das U.N. Biological significance of essential fatty acids.J Assoc Physicians India. 2006; 54: 309-319PubMed Google Scholar].Table 1Fatty acidsCategoryTrivial nameOmega-referencesSaturated FAsLauric acid12:0Myristic acid14:0Palmitic acid16:0Stearic acid18:0MUFAsPalmitoleic acid16:1 ω-9Oleic acid18:1 ω-9n-6 PUFAsLinoleic acidaEssential fatty acid, MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids (modified from: Stulnig TM. Int Arch Allergy Immunol 2003;132:310–321).18:2 ω-6γ-Linolenic acid18:3 ω-6Dihomo-γ-linolenic acid20:3 ω-6Arachidonic acid20:4 ω-6n-3 PUFAsα-Linolenic acidaEssential fatty acid, MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids (modified from: Stulnig TM. Int Arch Allergy Immunol 2003;132:310–321).18:3 ω-3Eicosapentaenoic acid20:5 ω-3Docosahexaenoic acid22:6 ω-3Any fatty acid (FA) has a carboxylic acid at one end and a methyl group with its carbon atom named omega (ω), the last letter of the Greek alphabet, at the other end. The omega reference system defines first the number of carbon atoms and the number of double bonds, separated by (:). When the closest double bond to the omega carbon is e.g. 3 carbon atoms away, the fatty acid is called omega (ω) or (n)-3.a Essential fatty acid, MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids (modified from: Stulnig TM. Int Arch Allergy Immunol 2003;132:310–321). Open table in a new tab Any fatty acid (FA) has a carboxylic acid at one end and a methyl group with its carbon atom named omega (ω), the last letter of the Greek alphabet, at the other end. The omega reference system defines first the number of carbon atoms and the number of double bonds, separated by (:). When the closest double bond to the omega carbon is e.g. 3 carbon atoms away, the fatty acid is called omega (ω) or (n)-3. Essential fatty acids constitute an important component of all cell membranes and influence membrane fluidity and the behavior of membrane-bound enzymes and receptors [[4]Das U.N. Biological significance of essential fatty acids.J Assoc Physicians India. 2006; 54: 309-319PubMed Google Scholar]. Borkman et al. [[5]Borkman M. Storlien L.H. Pan D.A. Jenkins A.B. Chisholm D.J. Campbell L.V. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids.N Engl J Med. 1993; 328: 238-244Crossref PubMed Scopus (790) Google Scholar] demonstrated in a group of patients undergoing coronary bypass surgery as well as in healthy controls that variations in insulin sensitivity are related to differences in the cell membrane content of long chain PUFAs within skeletal muscle phospholipids. In rats, activation of phospholipase A2, e.g., by ischemia/reperfusion induces break down of membrane phospholipids and the release of free fatty acids from the cell membrane lipid pool [[6]Hamamoto I. Nemoto E.M. Evans R.W. Mischinger H.J. Fujita S. Murase N. et al.Rat liver lipids during ex vivo warm and cold ischemia and reperfusion.J Surg Res. 1993; 55: 382-389Abstract Full Text PDF PubMed Scopus (18) Google Scholar]. In turn, certain PUFAs are utilized for the formation of various eicosanoids [[3]Stulnig T.M. Immunomodulation by polyunsaturated fatty acids: mechanisms and effects.Int Arch Allergy Immunol. 2003; 132: 310-321Crossref PubMed Scopus (165) Google Scholar]. Essential fatty acids have antibiotic-like actions; for instance, α-linolenic acid rapidly kills Staphylococcus aureus[[7]McDonald M.I. Graham I. Harvey K.J. Sinclair A. 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Weylandt K.H. Kahlke L. Wang J. Lobeck H. Tiegs G. et al.Omega-3 fatty acids alleviate chemically induced acute hepatitis by suppression of cytokines.Hepatology. 2007; 45: 864-869Crossref PubMed Scopus (139) Google Scholar] have recently provided evidence for inflammation-dampening effects of n-3 PUFAs in liver of transgenic fat-1 mice. These mice express a Caenorhabditis elegans desaturase endogenously; therefore they are able to form n-3 PUFAs from n-6 PUFAs. Feeding the fat-1 mice a diet rich in n-6 and low in n-3 PUFAs resulted in significant enhancement of hepatic content of n-3 PUFAs, lowering of n-6: n-3 PUFA ratio and alleviation of chemically induced acute hepatitis compared with their wild type littermates. The decreased inflammatory response in fat-1 mice was associated with significantly reduced hepatic gene expression of TNF-α, interleukin-1β, interferon-γ and interleukin-6. 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In high concentrations they contribute to the formation of thrombi and the development of inflammatory disorders [[19]Simopoulos A.P. Essential fatty acids in health and chronic diseases.Forum Nutr. 2003; 56: 67-70PubMed Google Scholar]. Dietary supplementation with eicosapentaenoic and docosahexaenoic acids is associated with a reduced production of thromboxane A2 (TXA2), a potent platelet aggregator and vasoconstrictor, and leukotriene B4 (LTB4), a powerful inducer of inflammation and leukocyte chemotaxis and adherence. Concomitantly TXA3, a weak platelet aggregator and vasoconstrictor is increased. Moreover, they increase concentrations of PGI3, without decreasing PGI2 (both PGI2 and PGI3 are active vasodilators and inhibitors of platelet aggregation) and increase concentrations of LTB5, a weak inducer of inflammation and chemotaxis. Thus, high intake of n-6 PUFAs shifts the physiological state to one that is proinflammatory and prothrombotic with increases in blood viscosity, vasospasm, and vasoconstriction. In contrast, n-3 PUFAs yield antiinflammatory, antithrombotic, vasodilatory and hypolipidemic properties [19Simopoulos A.P. Essential fatty acids in health and chronic diseases.Forum Nutr. 2003; 56: 67-70PubMed Google Scholar, 21Goetzl E.J. Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation.Med Clin North Am. 1981; 65: 809-828PubMed Google Scholar, 22Samuelsson B. Arachidonic acid metabolism: role in inflammation.Z Rheumatol. 1991; 50: 3-6PubMed Google Scholar, 23Sinclair S. Levy G. Eicosanoids and the liver.Ital J Gastroenterol. 1990; 22: 205-213PubMed Google Scholar, 24Bogatcheva N.V. Sergeeva M.G. Dudek S.M. Verin A.D. Arachidonic acid cascade in endothelial pathobiology.Microvasc Res. 2005; 69: 107-127Crossref PubMed Scopus (102) Google Scholar]. 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C57/Bl6 mice fed a choline deficient diet were used as a model of microvesicular steatosis. Of note, the choline deficient diet is supplemented with methionine; therefore we did not observe manifestations of steatohepatitis. Ob/ob mice were used as a model of predominantly macrovesicular hepatic steatosis [[40]El-Badry A.M. Moritz W. Contaldo C. Tian