# The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $460,191

## Abstract

Project Summary
 Alcohol-related liver disease (ALD) is a very common health problem among alcohol drinkers. Multiple
genome-wide association studies have reproducibly identified a single nucleotide polymorphism (rs738409,
C→G) in the human patatin-like phospholipase domain containing 3 (PNPLA3) gene, which results in isoleucine
(I) to methionine (M) substitution at amino acid 148, as the most significant gene variant associated with a broad
spectrum of ALD ranging from steatosis, hepatitis, to cirrhosis to date. PNPLA3 is a lipid droplet-associated
protein that is most abundantly expressed in human liver, which has been shown to have triglyceride lipase and
retinyl palmitate hydrolase activities. However, the pathophysiology of the 148M variant of PNPLA3 in the liver
remains largely unclear. In this project, we have developed transgenic mouse models for both variants of human
PNPLA3 and validated the key features of human ALD in the 148M mouse model. We aim to further address the
molecular underpinning of the 148M mutation in the alcohol-induced hepatic inflammation and fibrosis using both
cell and animal models. It is expected that the mechanistic investigation in this application will provide direct
evidence of the causal relationship between the 148M variant and the associated liver pathology. Altogether, we
believe that this project is highly significant and innovative.

## Key facts

- **NIH application ID:** 10366395
- **Project number:** 1R01AA028506-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** X. Charlie Dong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $460,191
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366395

## Citation

> US National Institutes of Health, RePORTER application 10366395, The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury (1R01AA028506-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10366395. Licensed CC0.

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