非酒精性脂肪肝在人群中的致病率高达25.2%，已成为危害人们身体健康的重要因素。临床研究表明，2型糖尿病患者中高达55.5%的病人同时患有非酒精性脂肪肝，但致病原因还不完全清楚。我们前期的研究结果发现，在2型糖尿病小鼠的肝脏中，AMPK调控的TBC1D1蛋白的磷酸化水平会被显著性抑制。通过构建和分析磷酸化位点失活突变的TBC1D1(S231A)小鼠，我们发现在突变小鼠的肝脏中PPARγ蛋白的水平会显著性增加，并诱发肝脏中脂滴的融合和脂肪酸的沉积。因此我们提出AMPK-TBC1D1-PPARγ通路参与调控2型糖尿病背景下非酒精性脂肪肝发生的假说。我们将利用与AMPK-TBC1D1-PPARγ通路相关的细胞、小鼠模型深入解析AMPK-TBC1D1通路调控PPARγ蛋白水平的分子机制及非酒精性脂肪肝发生的致病机理。本项目的完成能为临床上相关药物的研发、相关疾病的预防和治疗提供新的理论依据。

Non-alcoholic fatty liver (NAFLD) has a pathogenic rate of 25.2% in the population, which has been become an important factor that harms people's health. The results of clinical studies show that up to 55.5% of patients with type 2 diabetes also have NAFLD, but the underlying cause is currently unclear. Our previous studies found that in the liver of type 2 diabetic mice, the phosphorylation level of TBC1D1 protein regulated by AMPK was significantly inhibited. By constructing and analyzing TBC1D1(S231A) knock-in mice with phosphorylation site inactivation mutation, we found that the level of PPARγ protein in the liver of mutant mice increased significantly, eventually leading to lipid droplet fusion and fatty acid deposition in the liver. Based on this, we propose the hypothesis that the AMPK-TBC1D1-PPARγ signaling pathway can regulate the occurrence of NAFLD in the context of type 2 diabetes. This project will further explore the molecular mechanism of AMPK-TBC1D1 pathway regulating PPARγ protein level and the pathogenesis of NAFLD via using AMPK, TBC1D1 hepatocyte knockout and diet-induced mouse models. It is hoped that the completion of this project can provide new theoretical basis for the development of clinically relevant drugs and the prevention and treatment of related diseases.