Involvement of macrophage mTORC1 and mTORC2 in the development of non-alcoholic fatty liver disease (NAFLD) induced by a diet rich in lipids, sucrose and fructose and carcinogen treatment.

• Grant number: 24/09406-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2024
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Ana Brandao Pires
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma, AP.TEM

Abstract

Evidence obtained in recent decades suggests that lipotoxicity and inflammation, through still undefined molecular mechanisms, are the main factors that link adipose tissue dysfunction to the development of non-alcoholic fatty liver disease (NAFLD), which comprises steatosis (NAFL), steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Although mTORC1 and mTORC2, from both hepatocytes and macrophages, are activated by pro-inflammatory and pro-fibrogenic molecules, the role of these complexes as mediators of the metabolic and secretory actions of these molecules has not yet been investigated in the development and progression of NAFLD. Preliminary results from our research group demonstrate that a diet rich in lipids, cholesterol, sucrose and fructose associated with carcinogen treatment (CCl4) - called DIN - is efficient in inducing NAFLD. Furthermore, we verified that the deletion of mTORC2, specifically in macrophages, does not interfere with the accumulation of lipids and fibrosis induced by DIN. However, the increase in inflammatory cytokines and enzymes related to de novo lipogenesis in the liver of mice subjected to DIN was attenuated by the deletion of mTORC2, suggesting its contribution to the development of NAFLD. Considering the results obtained to date and that mTORC1 activity regulates important metabolic processes - aerobic glycolysis, oxidative metabolism and mitochondrial biogenesis - associated with the polarization of macrophages for both the M1 and M2 phenotype, we propose to investigate the contribution of mTORC1 in macrophage development and progression of NAFLD.