# Mast Cell Regulation of Alcohol-Induced Liver Damage

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $227,844

## Abstract

Alcoholic liver injury (ALD) encompasses a vast array of etiologies and patients present with simple steatosis to
alcoholic steatohepatitis (ASH), alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma causing liver failure.
Studies have examined the effects of ALD pathology on hepatocytes; however, limited information is known
about the role of mast cells (MCs) and cross-talk with cholangiocytes during ALD progression. In non-alcoholic
fatty liver disease (NAFLD), senescent cholangiocytes display a senescence-associated secretory phenotype
(SASP), recruiting MCs to the liver where they interact with other liver cells. In patients with cholestasis and
NAFLD, MCs are found in high numbers in the periportal area surrounding senescent bile ducts. Inhibition of
MC-histamine (HA) ameliorates disease phenotypes. In MC-deficient mice (KitW-sh) subjected to Western Diet,
there is resolution of NAFLD phenotypes. Stem cell factor (SCF) is a SASP upregulated in cholestatic patients
and increased in damaged cholangiocytes during NAFLD. SCF interacts with the receptor, c-Kit, (present on
MCs), and SCF/c-Kit is a prime chemoattractant pathway for MC migration. Inhibition of hepatic SCF using Vivo-
Morpholino treatment decreases MC migration and cholestatic liver phenotypes in Mdr2-/- mice, and inhibition of
SCF blocks MC migration toward damaged cholangiocytes, in vitro. In chronic hepatitis, MC degranulation and
HA secretion are upregulated and increased SCF/c-Kit expression positively correlates to HA. Studies have
demonstrated the prominent role for MCs during NAFLD and non-alcoholic steatohepatitis; however, no studies
have been performed to understand the contribution of MCs or crosstalk with cholangiocytes during ALD. The
premise of our exploratory study is built on preliminary data demonstrating that (i) MC presence surrounding
bile ducts increases in ASH patients; (ii) in mice fed ethanol (EtOH), serum HA and SCF increase; (iii) KitW-sh
mice fed EtOH have reduced hepatic steatosis and inflammation and (iv) SCF gene expression increases in
cholangiocytes, but not in hepatocytes in mice fed EtOH. Based on these findings, we propose the novel
hypothesis that during ALD, damaged cholangiocytes secrete increased SCF that recruits c-Kit-positive MCs to
the liver promoting steatosis, ductular reaction, inflammation and fibrosis by paracrine interactions with resident
liver cells and increased HA signaling. To evaluate our hypothesis, we propose the following specific aims:
Specific aim 1: To demonstrate that ALD liver phenotypes are dependent on MC-HA signaling via biliary SCF
and MC c-Kit interaction; and Specific aim 2: To test MC stabilizers on the progression of ALD in rodent models.
We will evaluate our aims using human tissues from ALD and control and organoids built from human cells (with
assistance from co-I, Dr. Burcin Ekser) along with chronic plus binge EtOH rodent models (Bin Gao-NIAAA
model) with assistance from Dr. Gianfranco Alpini, colla...

## Key facts

- **NIH application ID:** 10539568
- **Project number:** 1R21AA030107-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Heather L Francis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $227,844
- **Award type:** 1
- **Project period:** 2022-08-18 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539568

## Citation

> US National Institutes of Health, RePORTER application 10539568, Mast Cell Regulation of Alcohol-Induced Liver Damage (1R21AA030107-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10539568. Licensed CC0.

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