Muoio Deborah M
Sarah W. Stedman Nutrition and Metabolism Center and Department of Medicine, Duke University, Durham, NC 27710, USA.
Biochim Biophys Acta. 2010 Mar;1801(3):281-8. doi: 10.1016/j.bbalip.2009.11.007. Epub 2009 Dec 1.
The term lipotoxicity elicits visions of steatotic liver, fat laden skeletal muscles and engorged lipid droplets that spawn a number of potentially harmful intermediates that can wreak havoc on signal transduction and organ function. Prominent among these so-called lipotoxic mediators are signaling molecules such as long chain acyl-CoAs, ceramides and diacyglycerols; each of which is thought to engage serine kinases that disrupt the insulin signaling cascade, thereby causing insulin resistance. Defects in skeletal muscle fat oxidation have been implicated as a driving factor contributing to systemic lipid imbalance, whereas exercise-induced enhancement of oxidative potential is considered protective. The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative. This review centers on mechanisms that connect lipid surplus to insulin resistance in skeletal muscle, as well as those that underlie the antilipotoxic actions of exercise. Emphasis is placed on recent studies that challenge accepted paradigms.
脂毒性一词让人联想到脂肪变性的肝脏、充满脂肪的骨骼肌以及肿胀的脂滴，这些会产生许多潜在有害的中间体，它们会对信号转导和器官功能造成严重破坏。在这些所谓的脂毒性介质中，突出的是长链酰基辅酶A、神经酰胺和二酰甘油等信号分子；其中每一种都被认为会激活丝氨酸激酶，从而破坏胰岛素信号级联反应，进而导致胰岛素抵抗。骨骼肌脂肪氧化缺陷被认为是导致全身脂质失衡的一个驱动因素，而运动诱导的氧化能力增强则被认为具有保护作用。过去十年的糖尿病研究主要集中在上述情况，事实上，该模型有强有力的实验证据支持，尽管大多是相关性的。这篇综述聚焦于将脂质过剩与骨骼肌胰岛素抵抗联系起来的机制，以及运动抗脂毒性作用的潜在机制。重点是那些挑战公认范式的最新研究。
