The effect of etomoxir on the mRNA levels of enzymes involved in ketogenesis and cholesterogenesis in rat liver.
The effects of acute treatment with 2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylate (etomoxir), an antiketonaemic and antidiabetic drug, on the mRNA levels of several regulatory enzymes of ketogenesis, cholesterogenesis, and fatty acid synthesis in rats were determined. In rats treated with etomoxir, mRNA levels for mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase and carnitine palmitoyl transferase I (CPT I) remained unchanged, while mRNA levels for carnitine palmitoyl transferase II (CPT II) significantly increased 2-fold. Injection of etomoxir produced no effect on the mRNA levels of cytosolic HMG-CoA synthase but increased the mRNA levels of HMG-CoA reductase 2.5-fold. Etomoxir led to a 3-fold increase in the mRNA levels of fatty acid synthase of rats under acute treatment. Rats fed with a fat diet significantly increased the expression of mitochondrial HMG-CoA synthase, CPT I and CPT II 3-fold in all cases, while 2-(diethylhexyl)phthalate (DEHP) produced increases in the expression of these genes (5-, 4- and 12-fold, respectively). The mRNA levels of HMG-CoA reductase were not changed by either DEHP or fat diet, while DEHP increased cytosolic HMG-CoA synthase 2.5-fold. DEHP did not change the mRNA levels for fatty acid synthase. It was concluded that etomoxir does not produce its hypoketonaemic, hypocholesteraemic or hypolipogenic effects through changes in the genetic expression of the regulatory enzymes of these pathways, but probably due to the shortage of their common substrate, acetyl-CoA, because of the inhibitory action on CPT I.
Asins
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G
Unit of Biochemistry, University of Barcelona, School of Pharmacy, Spain.
Serra
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D
Hegardt
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FG
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000096:biosynthesis*; D004852:Epoxy Compounds / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D007657:Ketone Bodies / Q000096:biosynthesis*; D008099:Liver / Q000201:enzymology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004852:Epoxy Compounds; D005227:Fatty Acids; D007657:Ketone Bodies; D012333:RNA, Messenger; D000105:Acetyl Coenzyme A; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase; C054207:etomoxir