Ethanol and oleate inhibition of alpha-ketoisovalerate and 3-hydroxyisobutyrate metabolism by isolated hepatocytes.
Ethanol inhibited glucose synthesis from alpha-ketoisovalerate by isolated rat hepatocytes without significant inhibition of flux through the branched-chain alpha-ketoacid dehydrogenase complex. Accumulation of 3-hydroxyisobutyrate, an intermediate in the catabolism of alpha-ketoisovalerate, was increased by ethanol, indicating inhibition of flux at the level of 3-hydroxyisobutyrate dehydrogenase. 3-Hydroxybutyrate caused the same effects as ethanol, suggesting inhibition was a consequence of an increase in the mitochondrial NADH/NAD+ ratio. Flux through the 3-hydroxyisobutyrate dehydrogenase was more sensitive to regulation by the mitochondrial NADH/NAD+ ratio than flux through the branched-chain alpha-ketoacid dehydrogenase. Oleate also inhibited glucose synthesis from alpha-ketoisovalerate, but marked inhibition of flux through the branched-chain alpha-ketoacid dehydrogenase complex was caused by this substrate.
Hu
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Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis 46202-5122.
Jaskiewicz
J A
JA
Harris
R A
RA
D020155:3-Hydroxybutyric Acid; D000818:Animals; D002210:Caprylates / Q000494:pharmacology; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D005934:Glucagon / Q000494:pharmacology; D045782:Hemiterpenes; D006885:Hydroxybutyrates / Q000378:metabolism* / Q000494:pharmacology; D007651:Keto Acids / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008239:Lysine / Q000494:pharmacology; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology*; D051381:Rats
D002210:Caprylates; D045782:Hemiterpenes; D006885:Hydroxybutyrates; D007651:Keto Acids; D009829:Oleic Acids; D019301:Oleic Acid; D000431:Ethanol; C001505:alpha-ketoisovalerate; D005934:Glucagon; D008239:Lysine; C020757:3-hydroxyisobutyric acid; C031492:octanoic acid; D020155:3-Hydroxybutyric Acid