Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance
Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance
复制标题
DOI：
10.1016/j.cmet.2007.01.002
复制
发表时间：
2007-03-01
期刊：
影响因子：
29
通讯作者：
Summers, Scott A.
中科院分区：
文献类型：
--
作者：
Holland, William L.;Brozinick, Joseph T.;Summers, Scott A.
胰岛素抵抗发生在20%-25%的人口中，这种情况是2型糖尿病的主要组成部分，也是心血管疾病和某些形式癌症的危险因素。在此，我们证明鞘脂神经酰胺是一种常见的分子中间体，将几种不同的病理性代谢应激（即糖皮质激素和饱和脂肪，但不包括不饱和脂肪）与胰岛素抵抗的诱导联系起来。此外，抑制神经酰胺合成可显著改善肥胖啮齿动物的葡萄糖耐量，防止糖尿病的发生。总的来说，这些数据有两个重要的含义。首先，他们指出不同的脂肪酸通过不同的机制诱导胰岛素抵抗，这些机制依赖于鞘脂合成。其次，他们确定了神经酰胺合成所需的酶，作为对抗营养过剩或糖皮质激素治疗引起的胰岛素抵抗的治疗靶点。
Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.