Hexanoate and octanoate inhibit transcription of the malic enzyme and fatty acid synthase genes in chick embryo hepatocytes in culture.
Hexanoate and octanoate inhibit the triiodothyronine (T3)-induced increases in the activities of malic enzyme and fatty acid synthase in chick embryo hepatocytes in culture. Butanoate was less effective as an inhibitor, and palmitate, stearate, and oleate had no effect or small stimulatory effects. Hexanoate and octanoate inhibited the lipogenic enzyme activities at a transcriptional step, and did so within 30 min of addition. Incubation for 2 h in the absence of fatty acid reversed the inhibition of transcription caused by hexanoate. The inhibitory effect of hexanoate was selective because DNA content and transcription of the glyceraldehyde-3-phosphate dehydrogenase and beta-actin genes were not inhibited. Hexanoate-mediated inhibition of transcription rates of the lipogenic genes was not correlated with an inhibition of binding of T3 to its nuclear receptor. 2-Bromooctanoate and carnitine stimulated the T3-induced accumulation of the mRNAs for malic enzyme and fatty acid synthase. The presence of hexanoate stimulated by 2- to 3-fold the increase caused by carnitine, suggesting that hexanoate and carnitine may regulate lipogenic gene expression by a common pathway. Hexanedioate, acetoacetate, beta-hydroxybutyrate, branched chain fatty acids, and branched chain keto acids had little or no effect on abundance of the lipogenic mRNAs. We suggest that the active inhibitor is a metabolite derived from hexanoate or octanoate, possibly an intermediate derived from an acyl-CoA derivative.
Roncero
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Department of Biochemistry, University of Iowa, Iowa City 52242.
Goodridge
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AG
D000199:Actins / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002208:Caproates / Q000494:pharmacology*; D002210:Caprylates / Q000494:pharmacology*; D002331:Carnitine / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D004347:Drug Interactions; D064429:Fatty Acid Synthases / Q000235:genetics*; D005934:Glucagon / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D008291:Malate Dehydrogenase / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014284:Triiodothyronine / Q000494:pharmacology
D000199:Actins; D002208:Caproates; D002210:Caprylates; D012333:RNA, Messenger; D014284:Triiodothyronine; C037652:hexanoic acid; C019279:2-bromooctanoic acid; D005934:Glucagon; D008291:Malate Dehydrogenase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D064429:Fatty Acid Synthases; C031492:octanoic acid; D002331:Carnitine