Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase and carnitine palmitoyltransferase II as potential control sites for ketogenesis during mitochondrion and peroxisome proliferation.
3-Thia fatty acids are potent hypolipidemic fatty acid derivatives and mitochondrion and peroxisome proliferators. Administration of 3-thia fatty acids to rats was followed by significantly increased levels of plasma ketone bodies, whereas the levels of plasma non-esterified fatty acids decreased. The hepatic mRNA levels of fatty acid binding protein and formation of acid-soluble products, using both palmitoyl-CoA and palmitoyl-L-carnitine as substrates, were increased. Hepatic mitochondrial carnitine palmitoyltransferase (CPT) -II and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase activities, immunodetectable proteins, and mRNA levels increased in parallel. In contrast, the mitochondrial CPT-I mRNA levels were unchanged and CPT-I enzyme activity was slightly reduced in the liver. The CoA ester of the monocarboxylic 3-thia fatty acid, tetradecylthioacetic acid, which accumulates in the liver after administration, inhibited the CPT-I activity in vitro, but not that of CPT-II. Acetoacetyl-CoA thiolase and HMG-CoA lyase activities involved in ketogenesis were increased, whereas the citrate synthase activity was decreased. The present data suggest that 3-thia fatty acids increase both the transport of fatty acids into the mitochondria and the capacity of the beta-oxidation process. Under these conditions, the regulation of ketogenesis may be shifted to step(s) beyond CPT-I. This opens the possibility that mitochondrial HMG-CoA synthase and CPT-II retain some control of ketone body formation.
Madsen
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L
Department of Clinical Biochemistry, Haukeland Hospital, University of Bergen, Norway. Lise.Madsen@ikb.uib.no
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D000085:Acetates / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D003998:Dicarboxylic Acids / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000502:physiology; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D020675:Peroxisomes / Q000201:enzymology* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000085:Acetates; D000214:Acyl Coenzyme A; D003998:Dicarboxylic Acids; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D013440:Sulfides; D014280:Triglycerides; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D019308:Palmitic Acid; C062079:1,10-bis(carboxymethylthiodecane); D002334:Carnitine O-Palmitoyltransferase; D006904:Hydroxymethylglutaryl-CoA Synthase