# Sexual dimorphism, hepatic mitochondrial adaptations, and hepatic steatosis

> **NIH VA I01** · KANSAS CITY VA MEDICAL CENTER · 2020 · —

## Abstract

Project Summary/Abstract
Hepatic steatosis (fatty liver) is a risk factor for type 2 diabetes, cardiovascular disease, and further liver injury,
all major health issues for Veterans. Currently there are 1.6 million women Veterans, a number predicted to
grow steadily making women's health issues a major concern going forward. Prior to menopause, women are
protected against steatosis, but risk dramatically increases after loss of ovarian function and accumulating
evidence shows that differences in estrogen signaling are a primary mediator. Physical inactivity and low
fitness also drive increased risk for hepatic steatosis and associated pathologies. In contrast, increased
physical activity and exercise protects and treats steatosis, even in obese patients. Abnormalities in hepatic
mitochondrial function strongly contribute to the pathology of steatosis and are likely a primary target for the
effects of physical activity and exercise to mitigate the condition, but mechanisms remain largely unknown.
Estrogen is likely the cause of protection against hepatic steatosis in female rodents but the direct effects of
estrogen signaling on hepatic mitochondria function have received little attention. Our recent findings show that
female mice display increased mitochondrial respiration, lower reactive oxygen species (H2O2) emission and
protection against steatosis in a sedentary condition compared to males. Female hepatic mitochondria
respiratory capacity was also more responsive to diet- and exercise-induced metabolic stress, but these
adaptive traits were partially diminished in mice with genetic ablation of mitochondrial turnover (biogenesis and
mitophagy). These data form our hypothesis that enhanced mitochondrial function in females is critical for their
inherent protection against steatosis and adaptive responses to metabolic stress. We will test the hypothesis
that estrogen signaling through estrogen receptor α (ERα) is obligatory for elevated hepatic mitochondrial
function and adaptability in females by driving enhanced mitochondrial biogenesis and mitophagy. A second
objective of this proposal will test if differences in bile acid (BA) metabolism provide protection against
steatosis in females. Female rodents display chronically higher serum and fecal BA levels, paired with higher
expression of hepatic genes controlling cholesterol/BA synthesis. Increasing rates of BA synthesis and fecal
excretion via BA sequestrant drugs and chronic CYP7a1 overexpression also prevent and treat hepatic
steatosis, suggesting a similar affect to what we see in female livers. Our preliminary data suggest that
estrogen and exercise synergize to increase BA synthesis and fecal excretion only in females. We will test the
hypothesis that trafficking of excess acetyl CoA away from de novo lipogenesis (synthesis of new fatty acids)
and towards BA synthesis and fecal loss during postprandial conditions is an additional mechanism that
protects females against hepatic steatosis....

## Key facts

- **NIH application ID:** 9891404
- **Project number:** 2I01BX002567-05
- **Recipient organization:** KANSAS CITY VA MEDICAL CENTER
- **Principal Investigator:** John P Thyfault
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891404

## Citation

> US National Institutes of Health, RePORTER application 9891404, Sexual dimorphism, hepatic mitochondrial adaptations, and hepatic steatosis (2I01BX002567-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891404. Licensed CC0.

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