Rev-erbα Mediates Steatosis in Alcoholic Fatty Liver Through Regulating Autophagy

Abstract AFL is a liver disease caused by long-term excessive drinking, it is characterized by steatosis. Understanding the regulatory mechanism of steatosis is crucial for the treatment of AFL. Rev-erbα has been implicated in regulation of lipid metabolism. However, the role and the underlying mechanisms of Rev-erbα in AFL remains unknown. In this study, the antagonists or agonists of Rev-erbα as well as Rev-erbα shRNA were applied in vitro and vivo. Triglyceride and lipid droplets accumulation were measured by using TG kit and ORO staining. Lipid synthesis related factor Srebp1c and lipid β-oxidation regulatory factor Pparα were measured by using Western blot, qRT-PCR and immunohistochemistry analysis. Autophagy activity was measured by western blot and electron microscope, and lysosomal probe was used to labeled lysosomal acidity. We observed that the expression of Rev-erbα was significantly increased in vivo and vitro, and Rev-erbα activation mediated steatosis in L-02 cells. then, inhibition/down-expression of Rev-erbα improved the triglyceride and lipid droplets accumulation and the abnormal expression of Pparα and Srebp1c through enhancing the autophagy activity. Furthermore, down-expression of Rev-erbα up-regulated the nuclear expression of Bmal1, which regulated the autophagy activity in vitro. Collectively, these findings indicate that Rev-erbα induces liver steatosis and leads to the progression of AFL. Our study reveals a novel steatosis regulatorymechanism in AFL and suggest that Rev-erbα might be a potential therapeutic target for AFL.