Evaluation of the role of ChREBP in macrophage metabolism and function in metabolic dysfunction-associated steatohepatitis

• Grant number: 24/19679-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2025
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Thauany Martins Tavoni
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease, AP.TEM

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a most severe form of metabolic dysfunction-associated steatotic liver disease (MASLD). The accumulation and inflammatory polarization of hepatic macrophages is considered a hallmark of progressive disease. Alterations in the metabolic profile of macrophages can profoundly influence their activation state and functionality, influencing various pathological processes. However, the cellular mechanisms that occurs during the activation of hepatic macrophages during MASH development remain partially unknown. The carbohydrate-responsive element-binding protein (ChREBP) is a fructose- glucose-responsive transcription factor that regulates glycolysis and lipogenesis in hepatocytes. ChREBP expression in LPS-activated macrophages prevents cytokine production and apoptosis, through modulation of the redox status. Therefore, the objective of the present study is to determine the effects of ChREBP on macrophage metabolism and function in MASH. To this end, control animals (ChREBPfl/fl) and animals with conditional deletion of ChREBP in myeloid cells/macrophages (ChREBP-/-) will be submitted to high-fat diets that induce MASLD and MASH, or a chow diet. Markers of the disease will be evaluated, such as steatosis, amount of triglycerides in the liver, inflammatory markers in the liver, hepatocyte ballooning, NAS score, fibrosis, and serum ALT and AST. Macrophages will be characterized in terms of glycolytic and lipogenic rates as well as mitochondria metabolism; phenotype markers comprising cytokine expression and tissue repair markers; lipid droplets will be evaluated by CARS microscopy. Regarding macrophage function, efferocytosis will be measured. The role of ChREBP in the metabolic and functional aspects of macrophages will also be validated in vitro.