Involvement of mTORC1 and mTORC2 in the control of the acetylation of proteins related to lipid metabolism in the liver of a model of steatohepatitis.

• Grant number: 22/02123-1
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): April 01, 2022
• Effective date (End): March 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Álbert Souza Peixoto
• 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

NAFLD comprises a wide spectrum of liver diseases varying from a simple hepatic lipid accumulation denominated as steatosis (nonalcoholic fatty liver [NAFL]), to a much more serious form of chronic liver disease denominated as nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation, hepatocyte damage and fibrosis. The mechanisms involved in NAFLD include excessive fat accumulation in hepatocytes, impaired mitochondrial function, oxidative stress, inflammation, cell damage, apoptosis, and fibrosis activation. Additionally, the discovery of post-translational modifications (PTMs) of proteins (PMPs) is another layer of protein regulation and amplified the complexity of the mechanisms involved in NAFLD. This process, known as acetylation, occurs in proteins involved in metabolism, thus regulating enzyme activity, or in histones, regulating gene transcription. It has been proposed that high intracellular acetyl-CoA levels as found upon increased carbon flux in de novo fatty synthesis, for instance, activates lysine acetyltransferases enhancing therefore protein acetylation. Acetyl-CoA, the sole donor of acetyl for protein acetylation, is produced at the cytosol and nucleus from either citrate or acetate by the actions of the enzymes ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member (ACSS2), respectively. Recent studies have shown that ACLY is a molecular target of mTORC2 in a breast cancer cell line and mTORC2, but not mTORC1, is required for ACLY-catalyzed acetyl-CoA production. Furthermore, mTORC2-Akt has been shown to phosphorylate and activate ACLY and up-regulate ACSS2 expression, thereby increasing cytosolic acetyl-CoA and protein acetylation in adipocytes. On the other hand, mTORC1 interacts with and phosphorylates p300 acetyltransferases and regulates de novo autophagy and lipogenesis in vitro. Therefore, mTOR complexes 1 and 2 have important roles in the acetylation of proteins by different mechanisms. Based on these findings, we will test the hypothesis that acetylation is one of the main post-translational mechanisms by which mTORC1 and mTORC2 regulate the transcription of genes related to lipid metabolism in hepatocytes with direct implications in the steatohepatitis. Therefore, we will investigate the impact of inhibiting mTORC1 and mTORC2 on the acetylation profile of transcription factors, histones and proteins with focus on lipid metabolism in hepatocytes. We will also screen among lysine acetyltranferases and deacetylases protein families for those that are regulated by mTORC2 and mTORC1. The main targets of these enzymes will be also investigated.