Effect of estriol (E3) treatment on substrate utilization by hepatocyte mitochondria

• Grant number: 24/10147-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Alicia Juliana Kowaltowski
• Grantee: Mariana Pacheco Teixeira de Carvalho
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Estrogens play crucial roles in various physiological functions, especially in sexualmaturity, reproduction, and post-menopause. Additionally, they play a central role in energymetabolism. This effect is clearly observed in humans and animal models with reduced levels ofestradiol (E2), where E2 replacement reverses several parameters related to the risk ofdeveloping diabetes and cardiovascular diseases.E2 is the most abundant estrogen in the circulation of adult females of reproductive age,and its effects on mitochondrial functions of metabolically relevant cells such as hepatocytes hasbeen extensively explored. Treatment with E2 improves mitochondrial function, includingcalcium homeostasis and regulation of energy metabolism, and reduces oxidative stress, whichmay have beneficial effects on aging and age-related metabolic diseases.In addition to E2, other estrogens also circulate in the body, such as estrone (E1) andestriol (E3). E1 is more prevalent post-menopause, while E3 reaches significant levels duringpregnancy. Although E3 is less studied than E2, there are indications that it may have beneficialeffects on cardiovascular health and endothelial function, suggesting a protective role incardiovascular diseases.Despite these indications, there is a surprising lack of studies focused on the impact of E1and E3 on mitochondrial function in hepatocytes. Understanding these effects is crucial, giventhe central role of the liver in metabolism and energy homeostasis regulation. The focus of thisproject is understanding the mechanisms by which E3 influences mitochondrial function. Resultscould provide valuable insights into the physiological impact of increased levels of this hormoneduring pregnancy and potentially lead to the development of new therapeutic approaches formetabolic diseases.This project aims to evaluate whether acute and/or chronic treatment with E3 modifiessubstrate utilization by AML12 hepatocytes, both in intact and permeabilized cells, usinganalyses of cellular and mitochondrial oxygen consumption. Additionally, the study willinvestigate the underlying mechanisms of these modifications, assessing protein content throughWestern Blots and gene expression through quantitative PCRs.