Role of Activin Receptor Type 2 (ActRII) in liver physiology and Implication in MASLD development: role of non-canonical PI3K-AKT-mTORC1 signaling

• Grant number: 24/04994-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 25, 2024
• End date: July 24, 2025
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Álbert Souza Peixoto
• Supervisor: Paul M Titchenell
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Pennsylvania, United States
• Associated to the scholarship: 22/02123-1 - 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., BP.PD

Abstract

The activin receptor (ActR - type I and II) signaling pathways play critical roles in regulating a wide range of physiological and pathological activities across tissues. ActRII mediates the actions of ligands such activins, growth differentiation factors (GDFs), and bone morphogenetic proteins (BMPs) by activating downstream signaling cascades including canonical (Smads2,3,4) and non-canonical pathways (PI3K-Akt-mTORC1/FoxO1). However, their precise roles in liver metabolism and the development of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are poorly understood. MASLD comprises a variety of liver diseases, including hepatic lipid accumulation (steatosis) and its inflammatory form (steatohepatitis), which frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). Given its global prevalence and health consequences, understanding the molecular pathways driving MASLD development is critical. The purpose of this study is to investigate the role of ActRII in the regulation of liver physiology as well as its involvement in the development of MASLD, emphasizing the characterization of ActRII signaling through the canonical and non-canonical pathways. Considering that many components of these signaling pathways are under a complex post-translational regulation via acetylation, we propose to perform an extensive profiling of those modifications. Our goal is to further elucidate the molecular mechanisms underlying ActRII actions in hepatocytes and role in MASLD development aiming to find novel targets to prevent and treat liver illnesses. This proposal will be executed under the supervision of Prof. Paul M. Titchenell from the Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America, a worldwide expert in PI3K-AKT signaling and liver disease. Two procedures will be employed to evaluate the effects of ActRII deletion in hepatocytes. The first protocol involves feeding mice normal or high-fat diets deficient in methionine and choline for four weeks after ActRII deletion, then measuring glucose homeostasis, lipid metabolism, liver inflammation, fibrosis, acetylation profile, and intracellular signaling pathways. In the second protocol, mice with double deletion of Akt1 and Akt2 will be treated with the ActRII antibody CDD866 to see how it affects these parameters.