Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Hepatology. 2013 Feb;57(2):525-32. doi: 10.1002/hep.26015. Epub 2012 Dec 6.
Sphingolipids are important structural components of cell membranes and act as critical regulators of cell function by modulating intracellular signaling pathways. Specific sphingolipids, such as ceramide, glucosylceramide, and ganglioside GM3, have been implicated in various aspects of insulin resistance, because they have been shown to modify several steps in the insulin signaling pathway, such as phosphorylation of either protein kinase B (Akt) or of the insulin receptor. We now explore the role of the ceramide acyl chain length in insulin signaling by using a ceramide synthase 2 (CerS2) null mouse, which is unable to synthesize very long acyl chain (C22-C24) ceramides. CerS2 null mice exhibited glucose intolerance despite normal insulin secretion from the pancreas. Both insulin receptor and Akt phosphorylation were abrogated in liver, but not in adipose tissue or in skeletal muscle. The lack of insulin receptor phosphorylation in liver correlated with its inability to translocate into detergent-resistant membranes (DRMs). Moreover, DRMs in CerS2 null mice displayed properties significantly different from those in wild-type mice, suggesting that the altered sphingolipid acyl chain length directly affects insulin receptor translocation and subsequent signaling.
We conclude that the sphingolipid acyl chain composition of liver regulates insulin signaling by modifying insulin receptor translocation into membrane microdomains.
神经酰胺等特定鞘脂已被证明能调节胰岛素信号通路中的多个步骤，如蛋白激酶 B（Akt）或胰岛素受体的磷酸化，因此它们与胰岛素抵抗的各个方面有关。鞘脂是细胞膜的重要结构成分，通过调节细胞内信号通路来发挥关键的调节细胞功能作用。我们现在通过使用不能合成非常长链酰基（C22-C24）神经酰胺的神经酰胺合酶 2（CerS2）基因敲除小鼠来探索神经酰胺酰基链长度在胰岛素信号中的作用。尽管胰腺分泌正常，但 CerS2 基因敲除小鼠表现出葡萄糖不耐受。肝脏中胰岛素受体和 Akt 的磷酸化均被阻断，但在脂肪组织或骨骼肌中则没有。肝脏中胰岛素受体磷酸化的缺乏与其不能转位到去污剂抗性膜（DRM）中有关。此外，CerS2 基因敲除小鼠中的 DRM 表现出与野生型小鼠明显不同的特性，表明改变的鞘脂酰基链长度直接影响胰岛素受体的转位和随后的信号转导。
我们的结论是，肝脏的鞘脂酰基链组成通过调节胰岛素受体向膜微区的转位来调节胰岛素信号。
