Impact of Estradiol on the Development of Metabolic Dysfunction-Associated Steatohepatitis

• Grant number: 24/09313-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: João Paulo Gabriel Camporez
• Grantee: Leticia Franco Amaro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The consumption of a high-fat diet largely contributes to the development of cardiometabolic risk, including atherogenic dyslipidemia, high blood pressure, cardiovascular diseases and type 2 diabetes mellitus, and generally the central factor of this syndrome is 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 cardiometabolic diseases is Fatty Liver Disease Associated with Metabolic Dysfunction (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 Steatohepatitis Associated with Metabolic Dysfunction (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).