Effects of tetradecylthiopropionic acid and tetradecylthioacrylic acid on rat liver lipid metabolism.
Studies of effects of 4-thia-substituted fatty acid analogues on rat liver lipid metabolism are described. With isolated hepatocytes tetradecylthiopropionate was shown to divert [1-14C]oleate from beta-oxidation into esterification, the total amount of [1-14C]oleate metabolized remaining unchanged. Tetradecylthiopropionyl-CoA was a good substrate for mitochondrial carnitine palmitoyltransferases I and II (EC 2.3.1.21), acyl-CoA oxidase (EC 1.3.3.6), for the microsomal (but not mitochondrial) glycerophosphate acyltransferase (EC 2.3.1.15), and for long-chain acyl-CoA dehydrogenase (EC 1.3.99.3). In isolated hepatocytes, its 4-thia-trans-2-enoic derivative, tetradecylthioacrylate, inhibits both beta-oxidation of, and incorporation of, [1-14C]oleate into lipids. In rat liver mitochondria tetradecylthiocrylate inhibited beta-oxidation. The degree of inhibition was not markedly increased by preincubation with tetradecylthioacrylate. Tetradecylthioacrylyl-CoA was a poor substrate for carnitine palmitoyltransferase I, and inhibited carnitine palmitoyltransferase II, microsomal glycerophosphate acyltransferase and acyl-CoA oxidase. It is concluded that the inhibitory effects of tetradecylthiopropionyl-CoA are expressed intramitochondrially, whereas primary sites of inhibition by tetradecylthioacrylyl-CoA are extramitochondrial.
Institute of Medical Biochemistry, Dental School, University of Oslo, Norway.
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Osmundsen
D000179:Acrylates / Q000494:pharmacology*; D000214:Acyl Coenzyme A / Q000494:pharmacology*; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000187:drug effects; D042962:Acyl-CoA Oxidase; D000818:Animals; D002250:Carbon Radioisotopes; D002334:Carnitine O-Palmitoyltransferase / Q000187:drug effects; D003066:Coenzyme A Ligases / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000187:drug effects; D007553:Isotope Labeling; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013440:Sulfides / Q000494:pharmacology*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D000179:Acrylates; D000214:Acyl Coenzyme A; D002250:Carbon Radioisotopes; D009829:Oleic Acids; D011422:Propionates; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013440:Sulfides; C091635:tetradecylthioacrylyl-coenzyme A; C062077:1-(carboxyethylthio)tetradecane; D019301:Oleic Acid; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D005992:Glycerol-3-Phosphate O-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase