# Characterizing zonated hepatocyte sexual dimorphism and its role in fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $485,750

## Abstract

Sex is a strong determinant of susceptibility and severity for many human diseases. Yet
it is often ignored as a biological variable. The liver is a sexually dimorphic organ, which leads to
significant differences liver disease outcomes between men and women. This includes non-
alcoholic fatty liver disease, which affects over 25% of the population. There are currently major
gaps in our understanding of what the sex differences are in the liver, the mechanism that drive
these differences, and the manifestations of sex differences on liver disease outcome.
 Besides sex differences, the liver is also known to have significant functional differences
along the liver lobule, the basic functional unit of the liver. Liver diseases including NAFLD also
show zonation along the lobule in their pathology. To date, little is known about whether sexual
dimorphism in the liver is evenly distributed along the liver lobule.
 We showed that more than half of sexually dimorphic hepatocyte genes show spatial
zonation across the liver lobule. Surprisingly these zonated sexual dimorphic genes are
asymmetrically distributed across sex and the lobule, which corresponds to zonated sex
differences in liver function. We showed that systemic signals that drive sex differences exhibit
clear zonated activity while local signals that drive zonation show clear sexually dimorphic
activity. Finally, we showed in a liver injury model that shows both zonated damage and sex
differences in outcomes that zonated sexual dimorphism in hepatocytes drives the sex
differences in the liver’s response to injury.
 Our hypothesis is that lobular zonation and sexual dimorphism in hepatocytes are
coordinately regulated by the interactions between local lobular signals including Wnts and
systemic signals including growth hormone. We propose a set of studies to 1) determine the
respective roles of local and systemic signals in establishing zonated sexual dimorphism in
hepatocytes; 2) characterize how zonated sexual dimorphism in hepatocytes change across
different reproductive stages of prepuberty, sexual maturity and menopause; and 3)
characterize sex differences in liver response to NAFLD across different reproductive stages.
The results of these studies will improve our understanding of how sex differences affect liver
disease susceptibility and progression.

## Key facts

- **NIH application ID:** 10588098
- **Project number:** 1R01DK131227-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Bruce Mao Zheng Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $485,750
- **Award type:** 1
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10588098

## Citation

> US National Institutes of Health, RePORTER application 10588098, Characterizing zonated hepatocyte sexual dimorphism and its role in fatty liver disease (1R01DK131227-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10588098. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*