Effects of ethanol on the metabolism of free fatty acids in isolated liver cells.
Ethanol inhibited the oxidation and enhanced the esterification of albumin-bound [1-(14)C]palmitate incubated with isolated rat liver cells. Ethanol decreased the conversion of [1-(14)C]palmitate to (14)CO(2) and (14)C-labeled ketone bodies and enhanced the incorporation of [1-(14)C]palmitate into glycerolipids, especially triglyceride; cholesteryl ester synthesis was unaffected. The half-maximal effective ethanol concentration for each of these processes was 6-10 micro g/ml and a maximum effect was produced by about 50 micro g/ml. Ethanol oxidation was required for each of these alterations, since the effects were completely abolished by pyrazole. The energy obtainable from ethanol oxidation was in excess of the energy deficit from decreased fatty acid oxidation. However, ethanol did not affect O(2) consumption, indicating that ethanol oxidation replaced the oxidation of both fatty acids and other substrates. Ethanol inhibited the citric acid cycle in the intact liver cells by 20-30%. The major site of inhibition was alpha-ketoglutarate oxidation. Results suggest that ethanol inhibited alpha-ketoglutarate dehydrogenase in the mitochondria of hepatocytes by elevating the mitochondrial NADH:NAD ratio. A minor site of inhibition of ethanol oxidation was detected between succinate and citrate. It is suggested that ethanol inhibits fatty acid oxidation in hepatocytes by competitive substrate oxidation, resulting in an increased availability of long-chain free fatty acids; this thereby enhances esterification, leading to accumulation of liver triglyceride.
D000818:Animals; D002247:Carbon Isotopes; D002855:Chromatography, Thin Layer; D002952:Citric Acid Cycle; D000431:Ethanol / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000032:analysis / Q000378:metabolism*; D006017:Glycolipids / Q000096:biosynthesis; D066298:In Vitro Techniques; D007656:Ketoglutaric Acids / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000096:biosynthesis
D002247:Carbon Isotopes; D005230:Fatty Acids, Nonesterified; D006017:Glycolipids; D007656:Ketoglutaric Acids; D007657:Ketone Bodies; D010169:Palmitic Acids; D014280:Triglycerides; D009243:NAD; D000431:Ethanol; D007658:Ketone Oxidoreductases