# Hormonal control of NASH development and progression

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

Abstract/Summary
Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of pathologies ranging from simple steatosis to
non-alcoholic steatohepatitis (NASH – steatosis, hepatocyte ballooning and inflammation, with or without
fibrosis). Highly prevalent in obese and diabetic patients, NASH is an independent risk factor for cardiovascular
disease, cirrhosis, and hepatocellular carcinoma, devastating diseases that are more prevalent in veterans than
in the general population. Women of reproductive age have lower rates of NASH; however, this protection is lost
after menopause when NASH rates equal or exceed those for men. Both clinical and experimental data indicate
that estrogen plays a major role in protecting women against NASH. Moreover, the protective effects of estrogen
may also extend to men via tissue-dependent aromatization of androgens to estrogens. Despite this knowledge,
the precise tissue-specific mechanisms for estrogen-mediated protection have not been directly investigated.
This proposal will focus on the interrelationship between estrogen and growth hormone (GH), specifically at the
level of the hepatocyte, where published literature and preliminary data generated by our group have led to the
HYPOTHESIS that the estrogen receptor, ER, as well as the GH receptor (GHR), are required to slow NASH
development in part by sustaining hepatocyte Stat5b activity. Studies will compare male and female mice with
adult-onset, hepatocyte-specific, knockdown of the estrogen receptor, ER or GHR alone, or in combination to:
SA1 Determine the role of ER in hepatocyte Stat5b action and its impact on hepatic function and physiology in
the presence and absence of GHR-mediated signaling; SA2 Determine if hepatocyte ER protects against diet-
induced NASH, in the presence and absence of GHR; SA3 Determine if hepatocyte ER and/or GHR play a role
in tamoxifen (TAM) induced NASH progression. Endpoint analysis includes assessment of 1) GH-axis function,
whole body metabolism, liver lipid content and pathology, 2) Hepatic response to acute GH challenge (western
blot analysis of downstream intracellular signals and 3) Hepatic cell-type specific gene expression using single
nuclei RNA-Seq (snRNA-Seq), a technique that provides important information on the potential crosstalk
between cell types within the liver, critical for NASH development. The outcomes of this project will generate
new mechanistic insights to identify future drug targets to prevent NASH progression in both male and female
veterans.

## Key facts

- **NIH application ID:** 10830286
- **Project number:** 5I01BX004448-06
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Rhonda D Kineman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830286

## Citation

> US National Institutes of Health, RePORTER application 10830286, Hormonal control of NASH development and progression (5I01BX004448-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10830286. Licensed CC0.

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