Characterization of mTORC2 role in the hepatic steatosis, steatohepatitis and hepatocellular carcinoma progression induced by PTEN deletion in hepatocytes

Abstract

Visceral obesity is associated with the development of several chronic metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), a group of progressive liver complications that comprises steatosis (NAFL), steatohepatitis (NASH), cirrhosis and hepatocarcinoma (HCC). Several studies indicate that lipogenesis, inflammation, oxidative stress and insulin resistance contribute significantly to the development of NAFLD. In the current project, we will investigate the role of mTORC2, an upstream regulator of Akt, in the NAFL-NASH-HCC progression induced by Pten deletion and therefore hyperactivation of the PI3K-Akt-mTORC1 pathway in hepatocytes. In this sense, C57BL6/J mice controls or bearing in hepatocytes genetic deletion of Pten associated or not with the deletion of Rictor, which is essential for mTORC2 activity (Pten/Rictor double flox) (Cre albumin) will be evaluated by body weight, food intake, glucose and insulin tolerance, hepatic mass, lipid (de novo lipogenesis, TAG synthesis and VLDL secretion) and glucose metabolism (gluconeogenesis and glycogen synthesis and degradation), cell proliferation, steatosis, mitochondrial morphology and function, inflammation (leukocyte infiltration, cytokine and lipid mediators content), intracellular insulin and Toll like receptor-NFkB signaling, oxidative stress, phosphoproteome, lipid composition (lipidomics), fibrosis and tumorigenesis.