Impact of estrogen receptor alpha on nonalcoholic fatty liver disease and liver energy metabolism

Author(s)

Felipe Garcia da Silva Sucupira

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-08-18

Examining board members

João Paulo Gabriel Camporez; Rafael Calais Gaspar; Leonardo dos Reis Silveira

• Advisor: João Paulo Gabriel Camporez

Abstract

Lifestyle and increased consumption of high-fat diet largely contribute to the development of obesity, insulin resistance, type 2 diabetes (DM2) and cardiovascular disease. One of the consequences of this lifestyle and high-fat diet is Non-Alcoholic Fatty Liver Disease (NAFLD), which affects about 30% of adults and up to 10% of children in developed countries. Cardiovascular diseases associated with metabolic complications, such as insulin resistance and obesity, are less frequent in young women than in men of the same age or in women after menopause. Women after menopause have a higher risk of glucose intolerance, insulin resistance, hyperlipemia and visceral fat accumulation. Several mechanisms are currently considered to cause insulin resistance, such as abnormal lipid metabolism and ectopic accumulation, mitochondrial dysfunction, inflammation and endoplasmic reticulum stress. In recent decades, data from clinical and experimental studies have revealed that estradiol contributes enormously to glycemic homeostasis. Indeed, reduced estrogen levels during menopause are associated with increased visceral fat and, in turn, metabolic diseases such as insulin resistance, T2DM, and cardiovascular disease. It has also been reported that women with Turner syndrome, without endogenous estrogen production, have a higher risk of developing NAFLD than women without the syndrome. Furthermore, recent studies have shown that the degree of liver fibrosis and/or the rate of progression to hepatocellular carcinoma (HCC) in patients with NAFLD is higher in postmenopausal women and men than in premenopausal women. These findings suggest that gender disparity in NAFLD is likely related to differences in sex hormones, making women more resistant to NAFLD progression than men. However, it remains unknown how estradiol is related to the development and progression of NAFLD. Since the liver is a central organ in the development of T2DM, the general objective of this project is to study (in vivo) the effects caused by the absence of estrogen receptor alpha (ERα) on hepatic energy metabolism using animals with ERα deletion specifically in the liver (Cre-Lox system). We can see that the absence of Erα promoted significant changes in glucose tolerance where the receptor knockout animals became about 15% less tolerant to glucose variations, greater accumulation of hepatic triglycerides, and significant changes in gluconeogenesis pathways. (AU)

• FAPESP's process: 21/02638-9 - Impact of estrogen receptor alpha on non-alcoholic fatty liver disease and liver energy metabolism
• Grantee: Felipe Garcia da Silva Sucupira
• Support Opportunities: Scholarships in Brazil - Master