Docosahexaenoic acid liver

Mectianism of Action A combination of ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that inhibits acyl coenzyme A l,2-diacylglycerol acyltransferase and increases peroxisomal oxidation in the liver. Therapeutic Effect Reduces the synthesis of triglycerides in the liver. 

Either native winterized or concentrated whole-body fish oils or fish liver oils have been utilized in most studies as dietary source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The physiological effects and possible health benefits of administered fish oils generally have been attributed to either EPA or DHA alone or to a synergistic effect between the two. As a result, there has been controversy over the contribution of individual fish oil constituents to particular pharmacological actions and the optimal dosages required for achieving established and/or suspected beneficial effects. The predominant marine triglyceride-derived m-3-fatty acids are all-cA-5,8,11,14,17-eicosapentaenoic acid (C20 5i3, EPA) and all-ci.v-4,7,10,13,16,19-docosa-hexaenoic acid (C22 6,3, DHA). 

Enzyme complexes occur in the endoplasmic reticulum of animal cells that desaturate at A5 if there is a double bond at the A8 position, or at A6 if there is a double bond at the A9 position. These enzymes are different from each other and from the A9-desaturase discussed in the previous section, but the A5 and A6 desaturases do appear to utilize the same cytochrome b5 reductase and cytochrome b5 mentioned previously. Also present in the endoplasmic reticulum are enzymes that elongate saturated and unsaturated fatty acids by two carbons. As in the biosynthesis of palmitic acid, the fatty acid elongation system uses malonyl-CoA as a donor of the two-carbon unit. A combination of the desaturation and elongation enzymes allows for the biosynthesis of arachidonic acid and docosahexaenoic acid in the mammalian liver. As an example, the pathway by which linoleic acid is converted to arachidonic acid is shown in figure 18.17. Interestingly, cats are unable to synthesize arachidonic acid from linoleic acid. This may be why cats are carnivores and depend on other animals to make arachidonic acid for them. Also note that the elongation system in the endoplasmic reticulum is important for the conversion of palmitoyl-CoA to stearoyl-CoA. 

Docosahexaenoic acid (DHA) is a long-chain highly unsaturated fatty acid that is abundant in fish oil and is a precursor of several eicosanoids. DHA has a lipid-lowering effect through the suppression of lipogenic gene expression in the liver of rodents (Ikeda et al., 1998 Park and Harris, 2003 Buckley et al., 2004). In this paper, we introduce the evaluation of the physiological function of DHA in diet-induced lipodystrophy model mice. 

Gronn, M., Christensen, E., Hagve, T.A. and Christophersen, B.O. (1991) Peroxisomal retro-conversion of docosahexaenoic acid (22 6(n-3)) to eicosapentaenoic acid (20 5(n-3)) studied in isolated rat liver cells. Biochim. Biophys. Acta. 1081 85-91. 

A double bond within the terminal seven carbon atoms can be present at o>-3 or co-6. y-Linolenic acid is an a>-6 EFA and a-linolenic acid an rw-3 EFA. Other co-3 EFA are eicosapentaenoic acid (EPA) and docosahexaenoic acid (EX)HA), both abundant in edible fish tissues. Vegetable oils are rich in rw-6 EFA (Table 18-4). Plants contain a-linolenic acid, which can be converted in the body to EPA and DOHA, but it is found within chloroplast membranes and not in seed oils hence, it may not be available in significant quantities in the diet. The a>-3 and o)-6 EFA have different metabolic effects (see below). Particularly rich sources of EPA are fishes (e.g., salmon, mackerel, blue fish, herring, menhaden) that live in deep, cold waters. These fishes have fat in their muscles and their skin. In contrast, codfish, which have a similar habitat, store fat in liver rather than muscle. Thus, cod liver oi I is a good source of EPA, but it also contains high amounts of vitamins A and D, which can be toxic in large quantities (Chapters 38 and 37, respectively). Shellfi.sh also contain EPA. Plankton are the ultimate source of EPA. 

Abedin L, Lien EL, Vingrys AJ, Sinclair AJ. The effects of dietary alpha-linolenic acid compared with docosahexaenoic acid on brain, retina, liver, and heart in the guinea pig. Lipids 1999 34(5) 475-482. 

Sinclair AJ, Crawford MA. The incorporation of linolenic acid and docosahexaenoic acid into liver and brain lipids of developing rats. Fed Exp Biol Soc Lett 1972 26 127-129. 

Smiths, Abraham S. Fatty acid synthesis in developing mouse liver. Arch Biochem Biophys 1970 136 112-121. Stinson AM, Wiegand RD. Anderson RE. Recycling of docosahexaenoic acid in rat retinas during n-3 fatty... 

The fact that such an elaborate system of DHA maintenance is in place suggests that its presence serves some important function in the retina. Otherwise, why not let the DHA levels fluctuate as a function of dietary intake On a similar issue Crawford and Sinclair (1972) found that proportions of arachidonic, docosatetraenoic, and docosahexaenoic acids in brain gray matter lipids were constant in over 30 species. In contrast, other tissues such as liver and muscle reflect species dietary intake (Crawford Sinclair, 1972). The fact that PUFAs comprise approx 7% (dry weight) of brain gray matter (Sinclair, 1975),... 

Nuclear SREBP activity is also controlled by several post-translational regulations including phosphorylation, acetylation, sumoylation and ubiquiti-nation (Bengoechea-Alonso and Ericsson, 2007 Eberle et ah, 2004). Several cross-talks with kinase-mediated signalling are likely to influence SREBP-lc in the liver in vivo. GSK3 is involved in the phosphorylation and subsequent ubiquitination of SREBP-lc (Punga et ah, 2006 Sundqvist et ah, 2005). PKA-dependent phosphorylation of SREBP-lc also reduces SREBP-lc activity (Lu and Shyy, 2006). Together with 26S proteasome, Erk-dependent pathways is involved in the reduction of nuclear SREBP-1 induced by docosahexaenoic acid (C22 6n-3) (Botolin et ah, 2006). 

No adverse side effects of fucoxanthin were reported in the mice study. Notably, in animal studies, fucoxanthin also appeared to stimulate liver to produce docosahexaenoic acid (DHA), a type of omega-3 fatty acid, at levels comparable to fish oil supplementation. The animal experiments with fucoxanthin stimulated researchers to recommend human clinical trials. In placebo-controlled trials, a supplement containing a 5% fucoxanthin (daily dosage 10 mg) did not reveal any harmful effects (Holt, 2008). Therefore, fucoxanthin may be considered as nontoxic, nonaller-genic, biocompatible, bioactive materials. 

Tsukui, T., Konno, K., Hosokawa, M., Maeda, H., Sashima, T., and Miyashita, K. (2007). Fucoxanthin and fucoxanthinol enhance the amount of docosahexaenoic acid in the liver of KKAy obese/diabetic mice /. Agric. Food Chem. 55,5025-5029. 

Sanders, T.A.B., Vickers, M., and Haines, A.R, Effect on blood lipids and hemostasis of a supplement of cod-liver oil, rich in eicosapentaenoic and docosahexaenoic acids, in healthy young men, Clin. Set, 61, 317, 1981. 

Fig. 2. The effect of y-linolenic acid (GLA) and a-linolenic acid (ALA) supplementations on the changes (%) of arachidonic acid (AA ) and docosahexaenoic acid (DHA ) in liver and brain phosphatidylethanolamine (PE).

Concentrations of n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids (LC-PUFA) in Liver and Heart of Piglets Fed Formulas Supplemented with Single-Cell Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) ... 

Abedin, L., Lien, E.L., Vingtys, A J., and Sinclair, A J. (1999) The Effects of Dietary a-Linolenic Acid Compared with Docosahexaenoic Acid on Brain, Retina, Liver, and Heart in the Guinea Pig, Lipids 34,475-482. 

Harris, M.A., Hansen, R.A., Vidsudhiphan, R., Koslo, Ji.. Thomas, J.B., Watkins, B.A., and Allen, K.G.D. (2001) Effects of Conjugated Linoleic Acids and Docosahexaenoic Acid on Rat Liver and Reproductive Tissue Fatty Acids, Prostaglandins and Matrix Metalloproteinase Production, Prostaglandins Leukot. Essent. Fatty Acids 65,23-29. 

Willumsen, N., Hexeberg, S, Skorve, J., Lundquist, M. Berge, R.K. (1993). J. Lipid Res. 34 13-22. Docosahexaenoic acid shows no triglyceride-lowering effects but increases the peroxisomal fatty acid oxidation in liver of rats. 

Dietary supplement of cod liver oil was studied in another group of men. A daily dose of 20 ml of cod liver oil, corresponding to 1.8 g eicosapentaenoic acid and 2.2 g docosahexaenoic acid, was given. The proportions of eicosapentaenoic acid and docosahexaenoic acid in platelet lipids were increased mainly at the expense of w6 unsaturated fatty acids. After three weeks with cod liver oil supplement, the mean bleeding time was significantly prolonged [176]. 

Not only are 9c, t and 10t,12c-18 2 isomers metabolized differently, but they also have distinct effects on the metabolism of other fatty acids. Although both isomers resulted in a decrease in the level of arachidonic acid in liver phospholipids of rats, only the 10t,12c-18 2 induced an increase in the C22 polyunsaturated fatty acid in the hver hpids (2). Similarly, CLA supplementation (as a mixture or the 10f,12c isomer) decreased the 18 2n-6 content in hver phospholipids of hamsters (6). At the same time, docosahexaenoic acid was also decreased and a similar pattern was observed in low density lipoprotein-triacylglycerols. Feeding a mixture of CLA for 42 d induced an inaease in the long-chain n-3 fatty acids in rat liver, i.e., 22 5 and 22 6 (7). 

Hagve TA, Christophersen BO (1986) Evidence for retroconversion of adrenic acid (22 4(n-6)) and docosahexaenoic acid (22 6(n-3)) in isolated liver cells. Biochim Biophys Acta 875 165-173... 

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