Effects of Hepatic Estrogen Receptor Alpha on the Development of Metabolic Dysfunction-Associated Steatohepatitis

• Grant number: 24/09336-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2024
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: João Paulo Gabriel Camporez
• Grantee: Sandro Leão Matos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Consumption of a high-fat diet largely contributes to the development of metabolic syndrome, which includes atherogenic dyslipidemia, high blood pressure, cardiovascular diseases and type 2 diabetes mellitus, with the central factor of this syndrome generally being the development of insulin resistance associated with obesity. It is possible to observe that these metabolic complications are less prevalent in young women than in men of the same age or postmenopausal women. Several mechanisms are currently considered to cause insulin resistance, such as abnormal lipid metabolism, ectopic lipid accumulation, mitochondrial dysfunction, in addition to inflammation and endoplasmic reticulum stress. Furthermore, another complication associated with metabolic diseases is Metabolic dysfunction-associated fatty liver disease (MAFLD). Furthermore, MAFLD can progress to a more severe stage, presenting characteristics such as macro and/or microvesicular steatosis, mixed lobular inflammatory infiltrate and hepatocellular ballooning in the centrilobular vein area (zone III), and may present fibrosis and Mallory bodies, being known this clinical condition as Metabolic dysfunction-associated steatohepatitis (MASH). In recent decades, clinical and experimental studies have revealed that estradiol (the most potent estrogen) contributes enormously to glycemic homeostasis, probably via the alpha isoform of its receptor (ER±). In fact, reduced estrogen concentration during menopause is associated with increased visceral fat and, in turn, metabolic diseases such as insulin resistance, diabetes and cardiovascular disease. The same phenotype is observed in female rodents that undergo ovariectomy, with this phenotype reverting after hormonal treatment with estradiol. As the liver is a central organ in the control of metabolic homeostasis, the general objective of this project is to study (in vivo) the function of estrogen receptor alpha (ER±) specifically in the liver in the development of MASH using animals with deletion of ER± specifically in the liver. (Cre-Lox system).