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 that uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane. Treatment of primary culture of rat preadipocytes for 24 h with 40 microM etomoxir, an irreversible inhibitor of carnitine 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 mitochondrial membrane potential was detected by flow cytometry. Etomoxir treatment modified neither L-CPT-I (liver-type) nor PPARalpha mRNA levels in preadipocytes. In contrast, mRNA expression of acyl-CoA oxidase (ACO), the rate-limiting enzyme of peroxisomal fatty acid beta-oxidation, whose transcription is controlled by PPARalpha, was significantly induced (1.3-fold induction, P = 0.015). These findings suggest that the effects of etomoxir were mediated by PPARalpha. Since it has been reported that the intracellular accumulation of lipids following the inhibition of CPT-I by etomoxir leads to a PPARalpha-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 studied whether reductions in the expression of UCP-3 could compromise this response, giving rise to lipotoxic effects on cells.
Cabrero
A
A
Departamento de Farmacología y Química Terapéutica, Núcleo Universitario de Pedralbes, Barcelona, E-08028, Spain.
Alegret
M
M
Sánchez
R
R
Adzet
T
T
Laguna
J C
JC
Vázquez
M
M
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology*; D007473:Ion Channels; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012333:RNA, Messenger; C000604391:Ucp2 protein, rat; C000604394:Ucp3 protein, rat; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir