THE EFFECT OF ETOMOXIR ON THE MESSENGER-RNA LEVELS OF ENZYMES INVOLVED IN KETOGENESIS AND CHOLESTEROGENESIS IN RAT-LIVER

The effects of acute treatment with 2-[6-(4-chlorophenoxy)hexyl]-oxira ne-2- (etomoxir), an antiketonaemic and antidiabetic drug, on the mRNA levels of several regulatory enzymes of ketogenesis, cholesterogenesi s, and fatty acid synthesis in rats were determined. In rats treated w ith 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 transfer ase II (CPT II) significantly increased 2-fold. Injection of etomoxir produced no effect on the mRNA levels of cytosolic HMG-CoA synthase bu t increased the mRNA levels of HMG-CoA reductase 2.5-fold. Etomoxir le d to a 3-fold increase in the mRNA levels of fatty acid synthase of ra ts under acute treatment. Rats fed with a fat diet significantly incre ased the expression of mitochondrial HMG-CoA synthase, CPT I and CPT I I 3-fold in all cases, while 2-(diethylhexyl)phthalate (DEHP) produced increases in the expression of these genes (5-, 4- and 12-fold, respe ctively). The mRNA levels of HMG-CoA reductase were not changed by eit her 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, h ypocholesteraemic or hypolipogenic effects through changes in the gene tic expression of the regulatory enzymes of these pathways, but probab ly due to the shortage of their common substrate, acetyl-CoA, because of the inhibitory action on CPT I.