# Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $537,781

## Abstract

Alcohol-associated liver disease (ALD) is a leading cause of chronic liver diseases and the predominant
cause of liver-related mortality in Western countries. Patients with ALD may develop a wide spectrum of
liver pathologies from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis,
and eventually hepatocellular carcinoma. Extensive research has been performed to study the impact of
alcohol on hepatocytes, stellate cells, and immune cells including Kupffer cells in ALD, but little is known
about how alcohol affects biliary epithelial cells (i.e., cholangiocytes), and how biliary damage may
contribute to the early and late stages of ALD pathogenesis. Recent studies have indicated that ductular
reaction occurs in patients with alcoholic hepatitis. We have previously shown in other models of hepatic
damage that the secretin (Sct)/secretin receptor (SR) axis is upregulated and plays a critical role in ductular
reaction/biliary senescence as well as contributes to hepatic fibrosis. Our preliminary data that ALD-induced
ductular reaction, biliary senescence, inflammation, and fibrosis were ameliorated in mice lacking the
Sct/SR axis, indicating a crucial role for the SCT/SR axis during the pathogenesis of ALD. We propose the
novel central hypothesis that the SCT/SR signaling axis is a key for mediating the senescent, profibrogenic
biliary phenotype that contributes to the progression of hepatic inflammatory cell infiltration and subsequent
fibrosis during the course of the pathogenesis of ALD. To test our hypothesis, we will pursue the following
specific aims. In Specific aim #1, we will determine that activation of SCT/SR axis-dependent ductular
reaction and biliary senescence plays a key role in the induction of liver inflammation that drives hepatic
fibrosis during the pathogenesis of ALD. In specific aim #2, we will evaluate if therapeutic inhibition of the
SCT/SR axis can prevent and limit the progression of ALD. Completion of the proposed studies will
elucidate the translational mechanism on the role of SCT/SR axis in the promotion of local and systemic
responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype, biliary senescence,
hepatobiliary inflammation and fibrosis during the progression of ALD.

## Key facts

- **NIH application ID:** 10457005
- **Project number:** 5R01AA028711-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Gianfranco D Alpini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $537,781
- **Award type:** 5
- **Project period:** 2020-09-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457005

## Citation

> US National Institutes of Health, RePORTER application 10457005, Alcohol-induced hepatotoxicity - implications of secretin/secretin receptor axis (5R01AA028711-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457005. Licensed CC0.

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