Schaffer Jean E
Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Curr Opin Lipidol. 2003 Jun;14(3):281-7. doi: 10.1097/00041433-200306000-00008.
This review will provide the reader with an update on our understanding of the adverse effects of fatty acid accumulation in non-adipose tissues, a phenomenon known as lipotoxicity. Recent studies will be reviewed. Cellular mechanisms involved in the lipotoxic response will be discussed. Physiologic responses to lipid overload and therapeutic approaches to decreasing lipid accumulation will be discussed, as they add to our understanding of important pathophysiologic mechanisms.
Excess lipid accumulation in non-adipose tissues may arise in the setting of high plasma free fatty acids or triglycerides. Alternatively, lipid overload results from mismatch between free fatty acid import and utilization. Evidence from human studies and animal models suggests that lipid accumulation in the heart, skeletal muscle, pancreas, liver, and kidney play an important role in the pathogenesis of heart failure, obesity and diabetes. Excess free fatty acids may impair normal cell signaling, causing cellular dysfunction. In some circumstances, excess free fatty acids induce apoptotic cell death.
Recent studies provide clues regarding the cellular mechanisms that determine whether excess lipid accumulation is well tolerated or cytotoxic. Critical in this process are physiologic mechanisms for directing excess free fatty acids to specific tissues as well as cellular mechanisms for channeling excess fatty acid to particular metabolic fates. Insight into these mechanisms may contribute to the development of more effective therapies for common human disorders in which lipotoxicity contributes to pathogenesis.
本综述将向读者介绍我们对非脂肪组织中脂肪酸蓄积的不良影响（即脂毒性现象）的最新认识。将对近期研究进行综述。将讨论脂毒性反应所涉及的细胞机制。还将讨论对脂质过载的生理反应以及减少脂质蓄积的治疗方法，因为它们有助于我们理解重要的病理生理机制。
非脂肪组织中脂质蓄积过多可能发生在血浆游离脂肪酸或甘油三酯水平较高的情况下。或者，脂质过载是由于游离脂肪酸的摄入与利用不匹配所致。来自人体研究和动物模型的证据表明，心脏、骨骼肌、胰腺、肝脏和肾脏中的脂质蓄积在心力衰竭、肥胖症和糖尿病的发病机制中起重要作用。过量的游离脂肪酸可能会损害正常的细胞信号传导，导致细胞功能障碍。在某些情况下，过量的游离脂肪酸会诱导细胞凋亡性死亡。
近期研究为确定过量脂质蓄积是能被良好耐受还是具有细胞毒性的细胞机制提供了线索。在此过程中起关键作用的是将过量游离脂肪酸导向特定组织的生理机制以及将过量脂肪酸导向特定代谢命运的细胞机制。深入了解这些机制可能有助于开发出更有效的疗法，用于治疗脂毒性在发病机制中起作用的常见人类疾病。
