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Up-regulated delta 9-desaturase gene expression by hypolipidemic peroxisome-proliferating fatty acids results in increased oleic acid content in liver and VLDL: accumulation of a delta 9-desaturated metabolite of tetradecylthioacetic acid

Open AccessPublished:March 01, 1997DOI:https://doi.org/10.1016/S0022-2275(20)37263-1
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      In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (C13-S-acetic acid) and tetradecylthioacetic acid (C14-S-acetic acid), increase the mRNA levels of delta 9-desaturase both in a time- and dose-dependent manner. The increased delta 9-desaturase mRNA levels were accompanied by increased delta 9-desaturase activity and increased amounts of oleic acid (18:1 n-9) and delta 9-desaturated C14-S-acetic acid. delta 9-Desaturated C14-S-acetic acid was only detected in phospholipid and cholesterolester species after C14-S-acetic acid treatment. In contrast, C14-S-acetic acid was detected in all the different hepatic lipid fractions, but mainly in the phospholipids. Moreover, C13-S-acetic acid and C14-S-acetic acid were detected in both liver and very low density lipoprotein (VLDL). No delta 9-desaturated 3-thia fatty acid products, however, were found in VLDL. Administration of mono- and dicarboxylic 3-thia fatty acids to rats induced liver expression of the fatty acyl-CoA oxidase gene. After 1 week of C14-S-acetic acid treatment, the levels of fatty acyl-CoA oxidase mRNA increased 5-fold, whereas the delta 9-desaturase mRNA was increased about 1.8-fold. Both fatty acyl-CoA oxidase and delta 9-desaturase mRNA increased about 8-fold after 12 weeks of treatment with C14-S-acetic acid. In conclusion, this study demonstrates that C14-S-acetic acid increases rat delta 9-desaturase gene expression and activity and that changes in hepatic lipids, e.g., 18:1 n-9, are reflected in the VLDL. The peroxisome-proliferating monocarboxylic thia fatty acids are good substrates for desaturases, as delta 9-desaturated metabolites of monocarboxylated thia acids were formed in the liver. Modification of delta 9-desaturation, however, appears not to be related to peroxisome proliferation.

      REFERENCES

        • Skorve J.
        • Asiedu D.
        • Rustan A.C.
        • Drevon C.A.
        • Al-Shurbaji A.
        • Berge R.K.
        Regulation of fatty acid oxidation and trigylceride and phospholipid metabolism by hypolipidemic sulfur-substituted fatty acid analogues.
        J. Lipid Res. 1990; 31: 1627-1635
        • Al-Shurbaji A.
        • Skorve J.
        • Berge R.K.
        • Rudling M.
        • Bjorkhem I.
        • Berglund L.
        Effect of 3-thiadicar-boxylic acid on lipid metabolism in experimental nephrosis.
        Arterioscler. Thromb. 1993; 13: 1580-1586
        • Skorve J.
        • Al-Shurbaji A.
        • Asiedu D.
        • Bjorkhem I.
        • Berglund L.
        • Berge R.K.
        On the mechanism of the hypolipidemic effect of sulfur-substituted hexadec-anedoic acid (3-thiadicarboxylic acid) in normolipidemic rats.
        J. Lipid Res. 1993; 34: 1177-1185
        • Asiedu D.K.
        • Al-Shurbaji A.
        • Rustan A.C.
        • Bjorkhem I.
        • Berglund L.
        • Berge R.K.
        Hepatic fatty acid metabolism as a determinant of plasma and liver triacylglyc-erol levels.
        Eur. J. Biochem. 1995; 227: 715-722
        • Grav H.
        • Asiedu D.
        • Berge R.K.
        Gas chromatographic measurement of 3- and 4-thia fatty acids incorporated into various classes of rat liver lipids during feeding experiments.
        J. Chromatogr. B. Biomed. Appl. 1994; 658: 1-10
        • Lopez-Virella M.F.
        • Stone P.
        • Ellis S.
        • Colwell j.A.
        Cholesterol determination in high-density lipoproteins separated by three different methods.
        Clin. Chem. 1977; 23: 882-884
        • Asiedu D.
        • Aarsland A.
        • Skorve J.
        • Svardal A.
        • Berge R.
        Fatty acid metabolism in liver of rats treated with hypolipidemic sulfur-substituted fatty acid analogues.
        Biochim. Biophys. Acta. 1990; 1044: 211-221
        • Small G.M.
        • Burdett K.
        • Connock M.J.
        A sensitive spectrophotometric assay for peroxisomal acyl-CoA oxidase.
        Biochem. J. 1985; 227: 205-210
        • St. John L.C.
        • Lund D.K.
        • Smith S.B.
        Fatty acid elongation and desaturation enzyme activities of bovine liver and subcutaneous adipose tissue microsomes.
        J. Anim. Sci. 1991; 69: 1064-1073
        • Folch J.
        • Lees M.
        • Sloane Stanley G.H.
        A simple method for the isolation and purification of total lipids from animal tissues.
        J. Biol. Chem. 1957; 226: 497-509
        • Kaluzny M.A.
        • Duncan L.A.
        • Merritt M.V.
        • Epps D.E.
        Rapid separation of lipid classes in high yield and purity using bonded phase columns.
        J. Lipid. Res. 1985; 26: 135-140
        • Christie W.W.
        Gas Chromatography and Lipids. A Practical Guide. The Oily Press, Air, Scotland..
        Gas Chromatography and Lipids. A Practical Guide. The Oily Press, Air, Scotland. The Oily Press, Scotland1989: 76-77
        • Poole C.F.
        • Poole S.K.
        Chromatography Today.
        Chromatography Today. Elsevier Science Publishers, The Netherlands. Elsevier Science Publishers, The Netherlands1991: 88-95
        • Chomczynski P.
        • Sacchi N.
        Single-step method of RNA isolation by acid guanidinium thiocyanate-phe-nol-chloroform extraction.
        Anal. Biochem. 1987; 162: 156-159
        • Aasland R.
        • Lillehaug J.R.
        • Male R.
        • josendal O.
        • Varhaug J.E.
        • Kleppe K.
        Expression of oncogenes in thyroid tumors: Coexpression of e-erbB2Jneu and c-erbE.
        Br. J. Cancer. 1988; 57: 358-363
        • Sambrook J.
        • Fritsch E.
        • Maniatis T.
        Molecular Cloning: a Laboratory Manual.2nd ed.Cold Spring Harbor Laboratory Press.
        Molecular Cloning: a Laboratory Manual. 2nd edition. Cold Spring Harbor Laboratory Press, New York. 2nd edn, text revision. Cold Spring Harbor Laboratory Press, New York1989: 86-94
        • Feinberg A.
        • Vogelstein P.
        A technique for radiolabeling DNA restriction fragments to high specific activity.
        Anal. Biochem. 1983; 132: 6-13
        • Feinberg A.P.
        • Vogelstein B.
        A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity.
        Anal. Biochem. 1984; 137: 266-267
        • Osumi T.
        • Ishii N.
        • Hashimoto T.
        Isolation and structural characterization of the rat acyl-CoA oxidase gene.
        J. Biol. Chem. 1987; 262: 8138-8143
        • Asiedu D.K.
        • Froyland L.
        • Vaagenes H.
        • Lie O.
        • Demoz A.
        • Berge R.K.
        Long term effect of tetradecyl-thioacetic acid: a study on lipid profile and fatty acid composition and oxidation in different rat organs.
        Biochim. Biophys. Acta. 1996; 1300: 86-96
        • GÕttlicher Mv
        • Demoz A.
        • Svensson D.
        • Tollet P.
        • Berge R.K.
        • Gustafsson J-A
        Structural and metabolic requirements for activators of the peroxisome prolif-erator activated receptor.
        Biochem. Pharmacol. 1993; 46: 2177-2184
        • Tugwood J.D.
        • Issemann I.
        • Anderson R.G.
        • Bun-dell K.R.
        • McPheat W.L.
        • Green S.
        The mouse peroxisome proliferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene.
        EMBO J. 1992; 11: 433-439
        • Berge R.K.
        • Aarsland A.
        • Kryvi H.
        • Bremer J.
        • Aar-saether N.
        Alkylthio acetic acids (3-thia fatty acids)-a new group of non-oxidizable peroxisome-inducing fatty acid analogues-II. Dose-response studies on hepatic peroxisomal and mitochondrial changes and long-chain fatty acid metabolizing enzymes in rats.
        Biochem. Pharmacol. 1989; 38: 3969-3979
        • Demoz A.
        • Vaagenes H.
        • Aarsaether N.
        • Hvattum E.
        • Skorve J.
        • Skorve M.
        • GÕttlicher J.
        • Lillehaug J.R.
        • Gibson G.G.
        • Skorve J.
        • Gustafsson J-A.
        • Hood S.
        • Berge R.K.
        Coordinate induction of hepatic fatty acyl-CoA oxidase and P4504A1 in rat after activation of the peroxisome proliferator-acti-vated receptor (PPAR) by sulphur-substituted fatty acid analogues.
        Xenobiotica. 1994; 24: 943-956
        • Diczfalusy U.
        • Eggertsen G.
        • Alexson S.E.H.
        Clofibrate treatment increases stearoyl-CoA desaturase mRNA level and enzyme activity in mouse liver.
        Biochim. Biophys. Acta. 1995; 1259: 313-316
        • Landschulz K.T.
        • Jump D.B.
        • MacDougald O.A.
        • Lane M.D.
        Transcriptional control of the stearoyl-CoA desaturase-1 gene by polyunsaturated fatty acids.
        Biochem. Biophys. Res. Commun. 1994; 200: 763-768
        • Berge R.K.
        • Hvattum E.
        Impact of cytochrome P450 system on lipoprotein metabolism. Effect of abnormal fatty acids (3-thia fatty acids).
        Pharmacol. Ther. 1994; 61: 345-383
        • Viscardi R.M.
        Role of fatty acids in lung development.
        J. Nutr. 1995; 125: 1645S-1651S