mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma

• Grant number: 20/04159-8
• Support type: Research Projects - Thematic Grants
• Duration: September 01, 2021 - August 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal researcher: William Tadeu Lara Festuccia
• Grantee: William Tadeu Lara Festuccia
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Assoc. researchers: Alexandre Alarcon Steiner ; Giuseppe Palmisano ; Isaias Glezer ; Karina Thieme ; Mathieu Laplante ; Naima Moustaid-Moussa ; Sayuri Miyamoto
• Associated grant(s): 21/10469-2 - Multi-User equipment approved in grant 20/04159-8: spectrophotometer Synergy, AP.EMU
• Associated scholarship(s): 21/11108-3 - Technical training in crossing and genotyping of genetically modified mice., BP.TT

Abstract

Evidence gathered in the last decades suggests that lipotoxicity and inflammation, through still not completed defined molecular mechanisms, are the main factors connecting adipose tissue dysfunction to the development nonalcoholic fatty liver disease (NAFLD), a group of liver diseases that comprises from a simple hepatic steatosis (NAFL) to more severe steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). We propose herein to molecularly characterize mTORC1 and mTORC2 biology in hepatocytes and macrophages with a special emphasis in their involvement in the development of NAFL and its progression to NASH and HCC. For this, we will perform hepatocyte and macrophage mTORC1 (Raptor) and mTORC2 (Rictor) gain and loss of function experiments in vitro in primary cells and in vivo in two different mouse models of NAFLD induced either genetically through hepatocyte deletion of PTEN or through the intake of a high-fat, high-cholesterol, high-sucrose, high-fructose diet associated to weekly injections of a carcinogen, denominated altogether as diet-induced NAFLD (DIN). By employing imaging techniques, molecular biology tools and metabolic assays combined with powerful state-of-the-art OMICS (lipidomics, phosphoproteomics, acetylomics and transcriptomics), we will investigate the role of mTORC1 and mTORC2 in the regulation of the following inter-related processes in the NAFL-NASH-HCC progression: lipid metabolism and lipotoxicity; glucose homeostasis and glucotoxicity; endoplasmic reticulum and oxidative stress; inflammation; mitochondrial and peroxisomal oxidative metabolism, reactive oxygen species production and function, autophagy, epigenetics, DNA mutagenesis and repair, and tumorigenesis. (AU)