激活TRPV1预防非酒精性脂肪肝的机制研究

Lipid metabolism disorders of the body, especially the liver caused by high-fat diet lead to nonalcoholic fatty liver disease (NAFLD). The current interventions fail to reduce the incidence of NAFLD and the associated mechanisms are not fully understood. It's urgent to study the relevant mechanisms and put forward a new intervention strategy. Our early study shows TRPV1 activation by capsaicin prevents NAFLD, but the mechanism is not clear. PPARs activation mediates autophagy enhancement and reduces triglyceride levels in the hepatocytes. Others and our previous studies show that the capsaicin increases autophagy in a variety of cell lines, while TRPV1 activation by capsaicin regulates the PPARs' functions with significant weight loss. We plan to use the high-fat diet-induced nonalcoholic fatty liver disease （NAFLD） in wild-type and TRPV1-/- mice model to further study the roles of TRPV1 activation by long-term dietary capsaicin on the progress of NAFLD and effects on lipogenesis and lipolysis in hepatocytes. We want to proof that TRPV1 activation prevents NAFLD through PPARδ-dependent autophagy enhancement and lipolysis in mice. The results will contribute to our understanding of the pathophysiology process of NAFLD and a new intervention and target of the NAFLD prevention.

高脂饮食导致机体尤其是肝脏的脂质代谢紊乱是引发非酒精性脂肪肝的重要原因，目前的干预措施并未能有效降低非酒精性脂肪肝的发病率，相关的机制也并未完全阐明，因此亟待完善相关的机制研究并提出新的干预策略。前期工作表明，辣椒素通过激活TRPV1可显著防治非酒精性脂肪肝，但机制未明。PPARs激活可介导自噬增强及显著减少肝细胞内甘油三酯的含量。他人及我们的前期研究表明，辣椒素可增强多种细胞株的自噬功能，而辣椒素通过激活TRPV1可调控PPARs的功能，从而减肥。我们计划使用高脂饮食诱导的非酒精性脂肪肝小鼠及TRPV1-/-小鼠模型进一步研究长期膳食辣椒素激活TRPV1对非酒精性脂肪肝的发生与进展及肝细胞脂质代谢的影响，明确TRPV1通过激活PPARδ，增强自噬以促进脂质分解的作用机制。研究结果有助于认识非酒精性脂肪肝发生与进展的病理生理过程，为非酒精性脂肪肝的防治提供新的干预方式和靶点。