丝氨酸/苏氨酸蛋白激酶Mst1通过细胞自噬途径调节非酒精性脂肪肝肝脏脂代谢的机制

The regulatory mechanism of triglycerides deposits is not clear in the hepatocytes for nonalcoholic fatty liver disease (NAFLD), which affects the effective drug treatment. Study found that autophagosome can promote triglycerides decomposition by intake and degradation, but the specific mechanism remains to be elucidated. Our preliminary work suggests that protein kinase Mst1 overexpression can activate key orignal-step molecules of autophagy within liver cells, enhance phagocytic fat effects, and improve hepatocytes lipid accumulation. So we speculate that Mst1 can promote hepatocellular lipophagy via autophagy original-stage.Mst1 as a molecule target, from the whole-cell-molecular level, confirming the correlation of Mst1 and lipophagy by a series of cell biology, molecular biology and lipid metabolism research technology，explaining the possible mechanism of Mst1 in autophagy start step for AMPK - mTOR - ULK1 protein complexes,and further illustrating the effects of above modulation influence on fat catabolism of hepatocytes. The study provides research proof and reveals that Mst1 molecule plays a key effect on the regulation network of hepatic lipid metabolism, which deepens the novel acknowledgement of NAFLD treatment mechanism.

非酒精性脂肪肝（NAFLD）肝细胞内甘油三酯沉积的调控机制并不明确从而影响了有效的药物治疗。研究发现自噬小体可通过对脂滴的摄取与分解促进甘油三酯的降解，但其具体机理尚未明晰。我们的前期工作提示丝氨酸/苏氨酸蛋白激酶Mst1在NAFLD小鼠模型中过表达可活化肝细胞内自噬起始步骤关键分子、增强噬脂现象、改善肝脏脂肪积存。故推测Mst1可通过激活自噬起始环节促进肝细胞内自噬小体的噬脂能力。课题拟以Mst1作为分子靶标，从整体-细胞-分子水平，综合采用一系列细胞生物学、分子生物学以及脂代谢研究技术手段，证实Mst1与噬脂效应的相关性，了解Mst1对自噬起始步骤中的AMPK-mTOR-ULK1蛋白复合物活性调节的可能机制，阐明上述修饰效应对肝细胞内脂肪分解代谢途径的影响。这项研究将为揭示Mst1分子在肝脏脂代谢调节网络中的关键作用提供实验依据，也将深化对以自噬为切入点的NAFLD治疗机制的新认识。

非酒精性脂肪肝（NAFLD）肝细胞内甘油三酯沉积的调控机制并不明确从而影响了有效的药物治疗。研究发现自噬小体可通过对脂滴的摄取与分解促进甘油三酯的降解，但其具体机理尚未明晰。.课题组证实1.细胞凋亡与自噬的重要调节分子丝氨酸/苏氨酸蛋白激酶（Mammalian sterile 20-like kinase 1,Mst1）在NAFLD患者肝组织及小鼠模型肝脏中表达下调，同时伴有肝脏脂肪过度积存。过表达Mst1可促进NAFLD鼠模型肝脏及细胞模型内的噬脂与脂解现象。机制研究证实，Mst1靶向AMPKα/mTOR-Raptor/ULK1环路发挥对自噬途径的调控，具体而言Mst1通过磷酸化AMPKα(Thr172位点)进而直接或间接活化ULK1（Ser317、Ser 555位点）以及mTOR-Rapor(Ser317位点)。在MST1表达的细胞模型中突变这些位点可引起脂类积存，因此提示Mst1可通过激活自噬起始环节促进肝细胞内自噬小体的噬脂能力。这项研究为揭示Mst1分子在肝脏脂代谢调节网络中的关键作用提供实验依据，进一步深化了以自噬为切入点的NAFLD治疗机制的新认识。2.小鼠脂肪组织特征性高表达miR-199a-5p并且通过外分泌作用输送到肝脏，通过调控MST1/AMPK/SREBP-1c通路影响肝脏的脂肪合成与分解。