MST1 Regulates Hepatocellular Lipophagy in Nonalcoholic Fatty Liver Disease

Abstract Background and Aims: Mammalia sterile 20-like kinase 1 (MST1) has recently been identified as an important regulator for the development of non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanism of MST1 functions remains elusive. The current study is aiming to elucidate the impact and potential mechanism of MST1 in the disease progression of NAFLD. MethodsThe correlation of MST1 expression with NAFLD was determined in liver biopsy samples obtained from NAFLD patients by western blotting and IHC. The gain and loss of function analysis of MST1 was evaluated by the utilization of adenovirus or lentivirus mediated gene transfer. The impact of MST1 in lipophagy was examined by tracking the target protein markers through confocal microscopy and electron microscopy. Interaction of MST1 with the signaling molecule AMPKα/mTOR/ULK1 was evaluated by immune-blotting, in vitro kinase analysis and phosphorylation assays.Results: MST1 expression was inversely correlated with the hepatocellular lipid accumulation in both NAFLD patients and a mouse model. Impaired lipophagy was observed in the liver of Mst1-/- mice on a high fat diet. Restoration of MST1 promoted lipophagy and lipolysis in hepatocytes and the NAFLD mouse model. Further mechanistic approaches revealed that MST1 functioned to re-establish the dysfunctional autophagy/lipophagy pathway through targeting the AMPKα/mTOR/ULK1 interplay network. MST1 directly or indirectly activated ULK1 through coordination of AMPKα and mTOR/Raptor signaling pathways. Conclusions: MST1 may modulate hepatic lipid metabolism through restoration of dysfunctional autophagy and lipophagy, and thus might serve as an important therapeutic target for NAFLD.