# Sexual dimorphism of acetaminophen-induced liver injury and regeneration

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $46,036

## Abstract

ABSTRACT
 Acetaminophen (acetyl-para-aminophenol or APAP) is the most commonly used pain reliever in the
United States, yet acetaminophen overdose is the leading cause of acute liver failure in the developed world.
Currently the only available treatments are N-acetyl cysteine (NAC), which only has a short window of
effectiveness, or ultimately liver transplant. Therefore, therapeutic alternatives to treat APAP overdose are
urgently needed in the clinic. This proposal will address this issue by deciphering the mechanisms of
sexual dimorphism of APAP-induced liver injury and repair, and to leverage this sexual dimorphism by
establishing how hormone therapy will accelerate liver recovery in both sexes following APAP overdose.
Sex hormones and their receptors have been implicated in driving sexual dimorphism in many liver processes.
Specifically, higher average levels of growth hormone (GH) secretion in females contributes to higher metabolic
activity in their livers. Consistent with the literature, our preliminary data support the higher resistance of female
mice to APAP, shown by reduced liver necrosis, cell death, and detection of serum injury markers compared to
males. Moreover, our single-cell RNA sequencing analyses reveal that female hepatocytes and endothelial cells
(ECs) express significantly higher levels of GH receptor and GH pathway activation than male cells, while males
have upregulated inflammatory and cell death pathway activation. In preparation for this application, we
generated preliminary data showing that GH treatment significantly and rapidly repairs the tissues of both males
and females following sub-lethal doses of APAP, as quantified by tissue necrosis, cell death, and mouse survival.
These key data suggest a sexually dimorphic liver regenerative advantage in females, which can be recapitulated
with GH treatment to induce recovery in males and accelerate recovery in females. Therefore, we hypothesize
that there is a sexual dimorphism in APAP sensitivity that we can leverage with the use of GH to
accelerate liver regeneration in both sexes. In this proposal, we will further examine the role of GH and its
pathway activation in hepatocytes and ECs following APAP overdose via single-cell RNA sequencing analysis
and hepatocyte and EC -specific GH receptor knockouts. We will leverage these findings to establish an optimal
GH therapy with identification of GH specific doses and time frame of effectiveness for each sex to mitigate liver
injury and accelerate liver regeneration with superior efficacy to the current standard-of-care NAC. Potential
additive therapeutic effect of combined GH/NAC treatment will be also determined. In conclusion,
understanding the biological mechanisms behind the sexual disparity in APAP-induced liver injury, subsequent
regeneration, and modulation by GH will provide the biological foundation to establish a GH therapy to treat
APAP overdose in both sexes, a currently unmet clinical need.

## Key facts

- **NIH application ID:** 10315150
- **Project number:** 1F31DK127606-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Elissa Everton
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315150

## Citation

> US National Institutes of Health, RePORTER application 10315150, Sexual dimorphism of acetaminophen-induced liver injury and regeneration (1F31DK127606-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10315150. Licensed CC0.

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