Schrauwen Patrick, Hinderling Vera, Hesselink Matthijs K C, Schaart Gert, Kornips Esther, Saris Wim H M, Westerterp-Plantenga Margriet, Langhans Wolfgang
Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands.
FASEB J. 2002 Oct;16(12):1688-90. doi: 10.1096/fj.02-0275fje. Epub 2002 Aug 21.
The physiological function of human uncoupling protein-3 is still unknown. Uncoupling protein-3 is increased during fasting and high-fat feeding. In these situations the availability of fatty acids to the mitochondria exceeds the capacity to metabolize fatty acids, suggesting a role for uncoupling protein-3 in handling of non-metabolizable fatty acids. To test the hypothesis that uncoupling protein-3 acts as a mitochondrial exporter of non-metabolizable fatty acids from the mitochondrial matrix, we gave human subjects Etomoxir (which blocks mitochondrial entry of fatty acids) or placebo in a cross-over design during a 36-h stay in a respiration chamber. Etomoxir inhibited 24-h fat oxidation and fat oxidation during exercise by approximately 14-19%. Surprisingly, uncoupling protein-3 content in human vastus lateralis muscle was markedly up-regulated within 36 h of Etomoxir administration. Up-regulation of uncoupling protein-3 was accompanied by lowered fasting blood glucose and increased translocation of glucose transporter-4. These data support the hypothesis that the physiological function of uncoupling protein-3 is to facilitate the outward transport of non-metabolizable fatty acids from the mitochondrial matrix and thus prevents mitochondria from the potential deleterious effects of high fatty acid levels. In addition our data show that up-regulation of uncoupling protein-3 can be beneficial in the treatment of type 2 diabetes.
人类解偶联蛋白3的生理功能仍不清楚。在禁食和高脂喂养期间，解偶联蛋白3会增加。在这些情况下，线粒体可利用的脂肪酸超过了其代谢脂肪酸的能力，这表明解偶联蛋白3在处理不可代谢脂肪酸方面发挥作用。为了验证解偶联蛋白3作为线粒体从线粒体基质输出不可代谢脂肪酸的转运体这一假说，我们采用交叉设计，让人类受试者在呼吸室内停留36小时期间服用依托莫西（它可阻断脂肪酸进入线粒体）或安慰剂。依托莫西抑制了24小时脂肪氧化以及运动期间的脂肪氧化，幅度约为14%-19%。令人惊讶的是，在服用依托莫西36小时内，人类股外侧肌中的解偶联蛋白3含量显著上调。解偶联蛋白3的上调伴随着空腹血糖降低以及葡萄糖转运蛋白4转位增加。这些数据支持了以下假说：解偶联蛋白3的生理功能是促进不可代谢脂肪酸从线粒体基质向外转运，从而防止线粒体受到高脂肪酸水平的潜在有害影响。此外，我们的数据表明，解偶联蛋白3的上调在2型糖尿病治疗中可能有益。
