tetracosahexaenoic-acid and docosapentaenoic-acid

The effects on lipid metabolism of four different n-3 highly unsaturated fatty acids (n-3HUFA) including eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid (DPA, 22:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and tetracosahexaenoic acid (THA, 24:6n-3) were compared in the HepG2 cell model. None of the n-3HUFAs affected the viability of the cells. THA exerted the strongest suppression on the synthesis of triacylglycerol and cholesteryl ester (ChE), and the order of the strength of suppression was found to be THA > DHA > DPA > EPA. The mRNA level of fatty acid synthase was suppressed by the n-3HUFAs and the order of the strength of suppression by n-3HUFAs was the same in both triacylglycerol and ChE synthesis. These findings support previous animal test results using EPA, DPA, and DHA. In conclusion, both the number of carbon atoms and double bonds in an n-3HUFA structure has an effect on lipid metabolism in HepG2 cells.

Topics: Cell Survival; Cholesterol Esters; Depression, Chemical; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acid Synthases; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Hep G2 Cells; Humans; Lipid Metabolism; RNA, Messenger; Structure-Activity Relationship; Triglycerides

The objective of this study was to determine the effect of 2,2-diphenyl-5-(4-[[(1 E)-pyridin-3-yl-methylidene]amino]piperazin-1-yl)pentanenitrile (SC-26196), a delta6-desaturase inhibitor, on PUFA metabolism in human cells. SC-26196 inhibited the desaturation of 2 microM [1-14C] 18:2n-6 by 87-95% in cultured human skin fibroblasts, coronary artery smooth muscle cells, and astrocytes. By contrast, SC-26196 did not affect the conversion of [1-14C]20:3n-6 to 20:4 in the fibroblasts, demonstrating that it is selective for delta6-desaturase. The IC50 values for inhibition of the desaturation of 2 microM [1-14C] 18:3n-3 and [3-14C]24:5n-3 in the fibroblasts, 0.2-0.4 microM, were similar to those for the inhibition of [1-14C 18:2n-6 desaturation, and the rates of recovery of [1-14C]18:2n-6 and [3-14C]24:5n-3 desaturation after removal of SC-26196 from the culture medium also were similar. SC-26196 reduced the conversion of [3-14C]22:5n-3 and [3-14C]24:5n-3 to DHA by 75 and 84%, respectively, but it had no effect on the retroconversion of [3-14C]24:6n-3 to DHA. These results demonstrate that SC-26196 effectively inhibits the desaturation of 18- and 24-carbon PUFA and, therefore, decreases the synthesis of arachidonic acid, EPA, and DHA in human cells. Furthermore, they provide additional evidence that the conversion of 22:5n-3 to DHA involves delta6-desaturation.

Topics: Carbon Radioisotopes; Cell Line; Docosahexaenoic Acids; Enzyme Inhibitors; Fatty Acid Desaturases; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Piperazines; Stearoyl-CoA Desaturase; Time Factors

The purpose of this study was to determine whether the formation of docosahexaenoic acid in human cells occurs through a pathway that involves 24-carbon n-3 fatty acid intermediates and retroconversion. Normal human skin fibroblasts synthesized radiolabeled docosahexaenoic acid from [1-(14)C]18:3n-3, [3-(14)C]22:5n-3, [3-(14)C]24:5n-3, and [3-(14)C]24:6n-3. The amount of docosahexaenoate formed was reduced in fibroblasts defective in peroxisomal biogenesis, by 90-100% in Zellweger's syndrome and by 50-75% in infantile Refsum's disease. Fatty acid elongation and desaturation were intact in these mutant cells. No decrease in radiolabeled docosahexaenoic acid production occurred in mutant fibroblasts defective in peroxisomal alpha-oxidation or mitochondrial beta-oxidation, or in normal fibroblasts treated with methyl palmoxirate to inhibit mitochondrial beta-oxidation. Therefore, the retroconversion step in docosahexaenoic acid formation occurs through peroxisomal beta-oxidation in normal human cells. These results demonstrate that the pathway for docosahexaenoic acid synthesis in human cells involves 24-carbon intermediates. The limited ability to synthesize docosahexaenoic acid may underlie some of the pathology that occurs in genetic diseases involving peroxisomal beta-oxidation.

Topics: alpha-Linolenic Acid; Cells, Cultured; Docosahexaenoic Acids; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Fibroblasts; Humans; Microbodies; Mutation; Oxidation-Reduction; Reference Values; Skin; Zellweger Syndrome