脂肪细胞外泌体miR-32通过AMPKα2介导脂肪细胞-肝细胞对话促进代谢相关脂肪性肝病的发生

肥胖是代谢相关脂肪性肝病（MAFLD）最常见的危险因素，也是MAFLD进展的驱动因素，肥胖导致MAFLD机制仍未阐明。脂肪细胞外泌体（AdExos）是脂肪和肝脏对话的新信使。我们前期发现，miR-32敲除显著改善高脂喂养小鼠的MAFLD。AdExos可以被肝细胞摄取并上调miR-32表达，荧光素酶报告实验证实AMPKα2是miR-32的下游靶点。我们提出科学假说：脂肪细胞外泌体miR-32通过靶向负调控肝脏AMPKα2，上调SREBP1-C促进肝脏脂质沉积，抑制PINK1/Parkin介导的线粒体自噬，促进MAFLD发生。本项目将结合体内外实验，通过miR-32过表达及低表达，利用脂肪特异性及全身性miR-32敲除小鼠，明确AdExos来源的miR-32如何调控肝脏脂质代谢及线粒体自噬，从脂肪和肝脏对话新视角揭示肥胖驱动MAFLD的新机制，并为MAFLD的临床防治提供新思路。

Obesity is the most common risk factor for metabolic associated fatty liver disease (MAFLD) and a driver of the progression of MAFLD. The mechanism of obesity-induced MAFLD remains elusive. Adipocyte exosomes (AdExos) are new messengers in the crosstalk between fat and liver. We previously found that miR-32 knockout significantly improved MAFLD in high-fat fed mice. AdExos derived miR-32 can be uptake by hepatocytes and the luciferase reporting assay confirmed that AMPKα2 was a downstream target of miR-32. We hypothesize that AdExos derived miR-32 promotes SREBP1-c-dependent lipogenesis and suppresses PINK1/Parkin-dependent mitochondrial autophagy through targeted inhibition of AMPKα2, which further contributes to the occurrence and development of MAFLD. This project will establish a direct role of miR-32 during hepatic steatosis in vivo and in vitro experiments by the loss-and gain-of-function approaches. Then the adipose tissue specificity and systemic miR-32 knockout mice model will be used to clarify that how AdExos derived miR-32 regulates hepatic lipid metabolism and mitochondrial autophagy during the development of MAFLD. Thus, our project will reveal a novel mechanism of obesity-induced MAFLD from the perspective of fat-liver communication and provide a new strategy for the clinical prevention and treatment of MAFLD.