Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme a synthase and carnitinepalmitoyltransferase II as potential control sites for ketogenesis during mitochondrion and peroxisome proliferation

3-Thia fatty acids are potent hypolipidemic fatty acid derivatives and mito chondrion and peroxisome proliferators. Administration of 3-thia fatty acid s to rats was followed by significantly increased levels of plasma ketone b odies, whereas the levels of plasma non-esterified fatty acids decreased. T he hepatic mRNA levels of fatty acid binding protein and formation of acid- soluble products, using both palmitoyl-CoA and palmitoyl-L carnitine as sub strates, were increased. Hepatic mitochondrial carnitine palmitoyltransfera se (CPT) -II and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase a ctivities, 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 mo nocarboxylic 3-thia fatty acid, tetradecylthioacetic acid, which accumulate s 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 activit ies involved in ketogenesis were increased, whereas the citrate synthase ac tivity was decreased. The present data suggest that 3-thia fatty acids incr ease both the transport of fatty acids into the mitochondria and the capaci ty of the p-oxidation process. Under these conditions, the regulation of ke togenesis may be shifted to step(s) beyond CPT-I. This opens the possibilit y that mitochondrial HMG-CoA synthase and CPT-II retain some control of ket one body formation. (C) 1999 Elsevier Science Inc.