Lipotoxicity of β-cells in obesity and in other causes of fatty acid spillover
Lipotoxicity of β-cells in obesity and in other causes of fatty acid spillover
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DOI：
10.2337/diabetes.50.2007.s118
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发表时间：
2001-02-01
期刊：
影响因子：
7.7
通讯作者：
Zhou, YT
中科院分区：
文献类型：
--
作者：
Unger, RH;Zhou, YT
瘦素的一个新功能是在营养过剩期间通过增加过剩脂肪酸的β-氧化代谢和减少脂肪生成来保护非脂肪组织免受长链脂肪酸(FAs)的非氧化代谢产物的影响。当这种保护系统失效时，非氧化代谢的有害产物，如神经酰胺，在非脂肪组织中增加，包括胰岛和心脏，并导致一氧化氮介导的脂毒性和脂细胞凋亡。非脂肪细胞中三酰甘油的含量为全面的非氧化代谢提供了有用的指标。在正常的动物组织中，三酰甘油维持在一个狭窄的范围内；即使当热量摄入过多时，FA诱导的代偿性氧化上调也能防止过度蓄积。然而，如果瘦素缺乏或如果瘦素受体(Ob-R)不起作用，这种自我调节系统就不起作用，非脂肪组织中三酰甘油的含量就会增加。这提供了过量FAs的来源，这些FAs进入非氧化代谢的潜在毒性途径，导致某些组织的细胞凋亡。在骨骼肌中，FA超负荷会导致胰岛素抵抗；在心肌中，FA会损害心脏功能；在胰岛中，FA会导致胰岛β细胞功能障碍、细胞凋亡和糖尿病。这些组织中的所有异常都可以被曲格列酮阻断，曲格列酮是FA积累的抑制剂。
A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the beta -oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in nonadipose tissues, including the pancreatic islets and heart, and cause nitric oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol content in nonadipocytes provides a useful index of overall nonoxidative metabolism. In normal animal tissue triacylglycerol is maintained within a narrow range; even when the caloric intake is excessive, compensatory FA-induced upregulation of oxidation prevents overaccumulation. However, if leptin is deficient or if leptin receptors (Ob-R) are nonfunctional, this autoregulatory system does not operate, and triacylglycerol content rises in nonadipose tissues. This provides a source of excess FAs that enter potentially toxic pathways of nonoxidative metabolism leading to apoptosis of certain tissues. FA overload in skeletal muscle causes insulin resistance; in myocardium, it impairs cardiac function; and in pancreatic islets, it causes beta -cell dysfunction, apoptosis, and diabetes. All abnormalities in these tissues can be blocked by troglitazone, an inhibitor of FA accumulation.