Effects of the Alpha Estrogen Receptor in the Liver on the Modulation of Autophagy and Insulin Resistance in MASH and MASLD Models

• Grant number: 25/07441-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2025
• End date: February 28, 2029
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: João Paulo Gabriel Camporez
• Grantee: Felipe Nunes de Camargo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The consumption of a fat-rich diet significantly contributes to the development of metabolic syndrome, which encompasses atherogenic dyslipidemia, arterial hypertension, cardiovascular diseases, and type 2 diabetes mellitus. Insulin resistance, often linked to obesity, is considered the central factor in this syndrome. Research suggests that these metabolic complications are less prevalent in young women compared to men of the same age group or postmenopausal women. Mechanisms such as ectopic lipid accumulation, mitochondrial dysfunction, inflammation, and endoplasmic reticulum stress are recognized as key contributors to insulin resistance. Another related complication is Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), which can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH). MASH is characterized by macro- and/or microvesicular steatosis, inflammation, hepatocellular ballooning, fibrosis, and Mallory bodies. Studies have demonstrated that estradiol, the most potent estrogen, plays a crucial role in glycemic homeostasis, likely mediated through the alpha isoform of its receptor (ER¿). During menopause, the decline in estrogen levels is associated with increased visceral fat and metabolic dysfunctions, including insulin resistance and cardiovascular diseases. A similar phenomenon is observed in ovariectomized female rodents, with hormonal treatment reversing these effects. Autophagy, another critical factor in metabolism, is an evolutionarily conserved process that recycles cellular components to maintain homeostasis. In the liver, impaired autophagy leads to triglyceride accumulation and the development of steatosis, a condition closely linked to insulin resistance. Given the liver's central role in metabolic regulation, this project aims to investigate (in vivo) the role of the estrogen receptor alpha (ER¿) in hepatic metabolism within MASLD and MASH models. This will be achieved using animals with liver-specific deletion of ER¿ via the Cre-Lox system.