Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, up-regulates uncoupling protein-3 mRNA levels in primary culture of rat preadipocytes

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters t hat uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane. Treatment of primary culture of rat pr eadipocytes for 24 h with 40 mu M etomoxir, an irreversible inhibitor of ca rnitine palmitoyltransferase I (CPT-I), up-regulated UCP-3 mRNA levels (3.6 -fold induction), whereas changes in UCP-2 mRNA levels were not significant . As a consequence of increased UCP-3 expression, a fall in the mitochondri al membrane potential was detected by flow cytometry. Etomoxir treatment mo dified neither L-CPT-I (liver-type) nor PPAR alpha mRNA levels in preadipoc ytes. In contrast, mRNA expression of acyl-CoA oxidase (ACO), the rate-limi ting enzyme of peroxisomal fatty acid beta-oxidation, whose transcription i s controlled by PPAR alpha, was significantly induced (1.3-fold induction, P = 0.015). These findings suggest that the effects of etomoxir were mediat ed by PPAR alpha. Since it has been reported that the intracellular accumul ation of lipids following the inhibition of CPT-I by etomoxir leads to a PP AR alpha-mediated metabolic response that increases the expression of genes involved in alternate fatty acid oxidation pathways, these results seem to implicate UCP-3 in this protective metabolic response. It remains to be st udied whether reductions in the expression of UCP-3 could compromise this r esponse, giving rise to lipotoxic effects on cells. (C) 1999 Academic Press .