Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cell. 2011 Sep 30;147(1):173-84. doi: 10.1016/j.cell.2011.08.034.
Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.
饱和脂肪酸（FA）对健康有不良影响，比不饱和 FA 更容易导致胰岛素抵抗和 2 型糖尿病，其中一些具有保护和有益的作用。饱和 FA 会激活 Jun N-末端激酶（JNK），而不饱和 FA 则不会，JNK 与肥胖和胰岛素抵抗有关，在小鼠和人类中均有体现。然而，目前尚不清楚饱和 FA 和不饱和 FA 是如何被区分的。我们现在证明，饱和 FA 通过激活 c-Src 来激活 JNK 并抑制胰岛素信号。FA 改变了 c-Src 的膜分布，导致其分配到细胞内膜亚域，在那里它可能被激活。相反，具有已知改善葡萄糖代谢作用的不饱和 FA 可防止 c-Src 的膜分配和激活，这依赖于其豆蔻酰化，并且阻断 JNK 的激活。摄入致糖尿病的高脂肪饮食会导致小鼠脂肪细胞去污剂不溶性膜亚域中 c-Src 的分配和激活。
