MST1 Regulates Hepatic Lipid Metabolism By Inhibiting SIRT1 Ubiquitination In Mice

With the increase in the global obesity population, the incidence of non-alcoholic fatty liver disease (NAFLD) is expected to increase. The molecular pathogenesis of NAFLD is complex and involves multiple genetic and environmental factors. Previous study showed mammalian sterile20-like kinase (MST1) may serve as target for the development of new therapies for diabetes. MST1 can prevent the development of novel therapies for diabetes through inhibiting the destruction of the β cells. However, the function of MST1 involved in liver lipid metabolism has remained elusive. Silent Mating Type Information Regulation 2 homolog 1(SIRT1), a nuclear NAD+-dependent protein deacetylase, the ortholog of the yeast Sir2 protein, has emerged as a key metabolic sensor in various metabolic tissues. SIRT1 overexpression in the liver protects against high fat diet (HFD)-induced metabolic damage by deacetylating SREBP-1c, thus decreasing its expression. But the mechanism between MST1 and SIRT1 still remains unknown. In this study, we report that the liver of Mst1 knockout (Mstl-/-) mice showed more severe liver metabolic damage under fasting and high-fat diet than that of control mice. And fasting induced hepatic MST1 expression in the real-time quantitative PCR test. However, the effect of fasting-induced hepatic SIRT1 increase was attenuated in Mstl-/- mice. MST1 overexpression inhibited Srebp-1c expression and increased the expression of antioxidant genes in primary hepatocytes. We also found that MST1 overexpression promoted SIRT1 expression, probably due to inhibiting SIRT1 ubiquitination. MST1 inhibits ROS production in primary hepatocytes. There were interactions between MST1 and SIRT1 when the co-immunoprecipitation experiment was performed. In summary, our study suggests that MST1 regulates hepatic lipid metabolism by inhibiting SIRT1 ubiquitination. This study is of great significance to make a better understand of non-alcoholic fatty liver disease and find the new therapy in the future.