# Growth Hormone Regulation of Sex Differences in Liver Metabolism

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2020 · $503,133

## Abstract

7. Project Summary/Abstract
Sex differences in the liver transcriptome are widespread in both mice and humans and are largely regulated by
growth hormone (GH). The long-term goal of this project is to elucidate these sex differences to better understand
the mechanistic underpinnings of the many clinically relevant sex differences impacted by GH; these include sex-
differences in hepatic drug and steroid metabolism and lipid metabolic profiles, and in the incidence and severity
of liver pathologies, such as non-alcoholic fatty liver disease (NAFLD) and liver fibrosis associated with
development of hepatocellular carcinoma. Our recent studies in the mouse model revealed that GH acts through
its sex-specific temporal patterns of pituitary secretion – pulsatile in males and persistent in females — and via GH-
stimulated activation of liver STAT5, to establish a sex-differential epigenomic environment that enables the sex-
specific actions of GH in the liver. We identified several thousand genomic regions marked as putative enhancers
that have sex-biased binding sites for STAT5 and other essential GH-regulated liver transcription factors; and we
showed that sex-specific deposition by Ezh1/Ezh2 of histone-H3 lysine 27 trimethyl marks (H3K27me3) is required
specifically for the repression of many female-biased genes in male liver. Further, more than 200 sex-specific, GH-
regulated and nuclear-enriched long, non-coding RNAs (lncRNAs) were discovered, and strong candidates for
regulation of the sex-differential deposition of H3K27me3 and other chromatin marks at sex-specific genes and
their enhancers were identified by analysis of a large panel of Diversity Outbred mouse livers. This project builds
on these advances to elucidate fundamental mechanisms that underlie the transcriptional and epigenetic regulation
by GH of sex-biased gene expression essential for normal liver function. The work proposed has two major aims:
1) to discover critical features that underpin sex-biased gene transcription associated with sex-biased liver disease
by identifying functionally active sex-biased enhancers, which harbor the majority of genetic risk factors for fatty
liver disease, and to elucidate their organization within chromatin loop domains and subdomains, and their
interactions with sex-biased gene promoters; and 2) to discover the role of sex-specific, GH-regulated lncRNAs in
establishing and maintaining the sex-differentiated chromatin states at sex-biased enhancers and genes to support
sex differences in liver gene transcription, and then elucidate their contributions to the protective effects of GH-
activated STAT5 against hepatic stresses that induce non-alcoholic fatty liver disease and other liver pathologies.
Together, this work will identify key mechanistic features that enable GH, and its sex-dependent plasma patterns,
to regulate the sex-biased expression of hundreds of genes that control liver metabolic processes with a major
impact on human health and l...

## Key facts

- **NIH application ID:** 10018890
- **Project number:** 5R01DK121998-02
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** DAVID J WAXMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,133
- **Award type:** 5
- **Project period:** 2019-09-16 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018890

## Citation

> US National Institutes of Health, RePORTER application 10018890, Growth Hormone Regulation of Sex Differences in Liver Metabolism (5R01DK121998-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10018890. Licensed CC0.

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