干预FAT/CD36对mTOR信号通路激活介导的肝胰岛素抵抗的影响及机制研究

Fatty acid translocase (FAT/CD36) is an important membrane glycoprotein that links lipid metabolism to inflammation, and also closely related to glucose metabolism and insulin resistance. Reducing FAT/CD36 expression in tissues is regarded as a new therapeutic strategy for metabolic disorders. Interestingly, FAT/CD36 deficiency increases insulin sensitivity in muscle and fat tiusse, but induces insulin resistance in the liver and exacerbates non-alcoholic fatty liver disease (NAFLD) in mice. The mammalian target of rapamycin (mTOR) pathway has received a lot of attention recently because of its central role in modulating cell proliferation and metabolism, as well as its involvement in insulin resistance. We have previously demonstrated that mTOR activation impairs insulin signaling pathway (IRS2/PI3K/AKT) and leads to hepatic insulin resistance. However, whether mTOR signaling pathway involves in hepatic insulin resistance caused by FAT/CD36 deficiency is largely unknown. This project is designed, in cultured cells and the FAT/CD36 gene knockout mouse model, to investigate 1) whether FAT/CD36 deficiency activates mTOR signaling pathway in liver resulting in hepatic insulin resistance.2) The molecular link between FAT/CD36 and mTOR pathway.

脂肪酸转运酶（FAT/CD36）是连接机体脂代谢和炎症的重要膜糖蛋白，又与糖代谢、胰岛素抵抗密切相关，针对 FAT/CD36 的有效干预被认为是治疗代谢性疾病的新策略。然而，干预 FAT/CD36 虽可改善脂肪、肌肉等组织的胰岛素敏感性，却会加重肝胰岛素抵抗和脂肪肝的发生。哺乳动物雷帕霉素靶蛋白（mTOR）是重要的细胞营养感受器，肝脏 mTOR 被激活是导致 IRS2/PI3K/AKT 胰岛素信号通路减弱的重要原因。干预 FAT/CD36 是否可通过影响肝脏 mTOR 而导致肝胰岛素抵抗？尚不清楚。 本项目拟通过体内外实验，探讨 FAT/CD36 与 mTOR 间的分子联系，试图从一个新的角度阐释干预 FAT/CD36 对肝胰岛素敏感性的影响及可能分子机制，为脂肪肝等代谢性疾病防治提供理论依据。

脂肪酸转运酶（FAT/CD36）是机体脂质代谢的重要调控蛋白，又与糖代谢、胰岛素抵抗密切相关，针对 FAT/CD36 的有效干预被认为是治疗代谢性疾病的新策略。然而，干预FAT/CD36 虽可改善脂肪、肌肉等组织的胰岛素敏感性，却会加重肝胰岛素抵抗和脂肪肝的发生。本项目旨在探讨FAT/CD36导致肝胰岛素抵抗的分子机制。实验结果发现干预 FAT/CD36 可抑制正常饮食下生理状态的胰岛素信号传导，这与炎症及mTOR信号通路无显著相关性。非常有趣的是，我们发现CD36缺乏会导致肝脏蛋白酪氨酸磷酸酶1B（PTP1B）表达异常增加以及PTP1B和胰岛素受体（IR）相互作用增强，从而导致胰岛素信号传导减少和葡萄糖代谢紊乱。此外，在缺乏CD36的小鼠的肝脏中发现内质网压力（ER stress）增加，而清除ER应激使CD36敲除小鼠肝脏的PTP1B表达正常化并恢复了胰岛素信号传导。我们的研究结果表明，CD36的缺失通过增强ER应激诱导的PTP1B / IR相互作用而损害了肝胰岛素信号传导，这在肝胰岛素抵抗进程中可能是关键步骤。