Samec S, Seydoux J, Russell A P, Montani J P, Dulloo A G
Department of Medicine, University of Fribourg, Rue du Musée 5, 1700 Fribourg, Switzerland.
Pflugers Arch. 2002 Oct;445(1):80-6. doi: 10.1007/s00424-002-0879-9. Epub 2002 Jul 17.
The uncoupling protein homologs UCP2 and UCP3 have been proposed as candidate genes for the regulation of lipid metabolism. Within the context of this hypothesis, we have compared, from fed and fasted rats, changes in gene expression of skeletal muscle UCP2 and UCP3 with those of carnitine palmitoyltransferase I and medium-chain acyl-CoA dehydrogenase, two key enzymes regulating lipid flux across the mitochondrial beta-oxidation pathway. In addition, changes in gene expression of peroxisome proliferator-activated receptor gamma, a nuclear transcription factor implicated in lipid metabolism, were also investigated. The results indicate that in response to fasting, the mRNA levels of UCP2, UCP3, carnitine palmitoyltransferase I and medium-chain acyl-CoA dehydrogenase are markedly increased, by three- to sevenfold, in the gastrocnemius and tibialis anterior (fast-twitch muscles, predominantly glycolytic or oxidative-glycolytic), but only mildly increased, by less than twofold, in the soleus (slow-twitch muscle, predominantly oxidative). Furthermore, such muscle-type dependency in fasting-induced transcriptional changes in UCP2, UCP3, carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase persists when the increase in circulating levels of free fatty acids during fasting is abolished by the anti-lipolytic agent nicotinic acid - with blunted responses only in the slow-twitch muscle contrasting with unabated increases in fast-twitch muscles. Independently of muscle type, however, the mRNA levels of peroxisome proliferator-activated receptor gamma are not altered during fasting. Taken together, these studies indicate a close association between fasting-induced changes in UCP2 and UCP3 gene expression with those of key regulators of lipid oxidation, and are hence consistent with the hypothesis that these UCP homologs may be involved in the regulation of lipid metabolism. Furthermore, they suggest that in response to fasting, neither the surge of free fatty acids in the circulation nor induction of the peroxisome proliferator-activated receptor gamma gene may be required for the marked upregulation of genes encoding the UCP homologs and key enzymes regulating lipid oxidation in fast-twitch muscles.
解偶联蛋白同源物UCP2和UCP3已被提出作为调节脂质代谢的候选基因。在此假设背景下，我们比较了喂食和禁食大鼠骨骼肌UCP2和UCP3的基因表达变化，以及肉碱棕榈酰转移酶I和中链酰基辅酶A脱氢酶（调节脂质通过线粒体β氧化途径通量的两种关键酶）的基因表达变化。此外，还研究了过氧化物酶体增殖物激活受体γ（一种与脂质代谢有关的核转录因子）的基因表达变化。结果表明，禁食后，腓肠肌和胫前肌（快肌，主要是糖酵解型或氧化糖酵解型）中UCP2、UCP3、肉碱棕榈酰转移酶I和中链酰基辅酶A脱氢酶的mRNA水平显著增加，增加了三到七倍，但比目鱼肌（慢肌，主要是氧化型）中仅轻度增加，增加不到两倍。此外，当抗脂解剂烟酸消除禁食期间游离脂肪酸循环水平的升高时，UCP2、UCP3、肉碱棕榈酰转移酶和中链酰基辅酶A脱氢酶在禁食诱导的转录变化中的这种肌肉类型依赖性仍然存在——只有慢肌中的反应减弱，而快肌中的增加未减弱。然而，与肌肉类型无关，禁食期间过氧化物酶体增殖物激活受体γ的mRNA水平没有改变。综上所述，这些研究表明禁食诱导的UCP2和UCP3基因表达变化与脂质氧化关键调节因子的变化密切相关，因此与这些UCP同源物可能参与脂质代谢调节的假设一致。此外，它们表明，对于快肌中编码UCP同源物和调节脂质氧化的关键酶的基因的显著上调，禁食期间循环中游离脂肪酸的激增和过氧化物酶体增殖物激活受体γ基因的诱导可能都不是必需的。
