MST1 Regulates Mouse Hepatic Gluconeogenesis By Promoting The Expression Of PEPCK

As the central organ of metabolism,liver is the major site for gluconeogenesis.Excessive activation of gluconeogenesis could cause metabolic disorders in the body and eventually lead to the Type 2 Diabetes Mellitus(T2DM).Phosphoenolpyruvate carboxykinase(PEPCK)is a rate-limiting enzyme in the hepatic gluconeogenesis pathway.It has been reported that model mice of diabetes mellitus infected with PEPCK shRNA adenovirus were significantly improved the poor conditions such as hyperglycemia and hyperinsulinemia.As one of the core components of Hippo signaling pathway,mammalian sterile line 20-like kinase 1(MST1)is a serine/threonine kinase,which is mainly involved in regulating cell proliferation and cycle,promoting cell apoptosis,inhibiting tumor growth and other biological processes.Previous study revealed that MST1 could inhibit Sterol Regulatory Element Binding Protein 1C(SREBP-1C)through Silent Mating Type Information Regulation 2 homolog 1(SIRT1)and improve the expression of antioxidant genes to regulate hepatic lipid metabolism.However,there are few studies on the role of MST1 in liver glucose metabolism.Our study found that the expression levels of Mstl mRNA in the liver of db/db diabetic mice were significantly higher than that of the control group db/m mice.MST1 overexpression enhanced glucose output in mouse primary hepatocytes.MST1 could promote the mRNA expression levels of Pepck by enhancing the activity of its promoter.Through interference experiments,we found that MST1 promoted the expression of PEPCK dependent on FOXO1.Besides,compared with wild-type mice,Mst11-global-knockout mice(Mst1-/-mice)showed weight loss and improvement metabolic capacity,such as increased oxygen consumption,carbon dioxide production and heat production.However,there no changes in glucose tolerance and insulin sensitivity in Mst1/-mice.In this study,MST1,one of the core components of the Hippo pathway,was associated with the mouse liver gluconeogenesis pathway,providing a new theoretical basis and target for the prevention and clinical treatment of diabetes in the future.