Cabrero A, Alegret M, Sánchez R, Adzet T, Laguna J C, Vázquez M
Departamento de Farmacología y Química Terapéutica, Núcleo Universitario de Pedralbes, Barcelona, E-08028, Spain.
Biochem Biophys Res Commun. 1999 Sep 16;263(1):87-93. doi: 10.1006/bbrc.1999.1332.
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.
解偶联蛋白（UCPs）是线粒体膜质子转运体，通过耗散跨膜质子梯度使呼吸与氧化磷酸化解偶联。用肉碱棕榈酰转移酶I（CPT-I）的不可逆抑制剂40微摩尔依托莫西对大鼠前脂肪细胞原代培养物处理24小时，上调了UCP-3 mRNA水平（诱导3.6倍），而UCP-2 mRNA水平变化不显著。由于UCP-3表达增加，通过流式细胞术检测到线粒体膜电位下降。依托莫西处理未改变前脂肪细胞中L-CPT-I（肝型）和PPARα mRNA水平。相反，过氧化物酶体脂肪酸β-氧化的限速酶酰基辅酶A氧化酶（ACO）的mRNA表达受到显著诱导（诱导1.3倍，P = 0.015），其转录受PPARα控制。这些发现表明依托莫西的作用是由PPARα介导的。由于已有报道称依托莫西抑制CPT-I后细胞内脂质积累会导致PPARα介导的代谢反应，增加参与替代脂肪酸氧化途径的基因表达，这些结果似乎表明UCP-3参与了这种保护性代谢反应。UCP-3表达降低是否会损害这种反应并对细胞产生脂毒性作用仍有待研究。
