# Progression from steatosis to steatohepatitis in alcoholic liver disease is enhanced by the risk allele of PNPLA3 via remodeling of lipid droplets and disruption of bioactive lipid composition

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $226,406

## Abstract

Project Summary/Abstract:
Alcoholic liver disease (ALD) is one of the main causes of chronic liver disease worldwide and accounts for up
to 48% of deaths associated with end stage liver disease in the United States 1. Compared to other types of liver
disease, there has been little progress in the pharmacological management of ALD. Factors contributing to a
lack of specific therapeutic targets include current suboptimal disease models and the gap in our knowledge of
mechanisms of susceptibility and tolerance to chronic alcohol exposure. We propose to bridge this gap by using
human stem cell and gene editing technology to study the most important genetic susceptibility factor involved
in ALD progression; the risk variant polymorphism of PNPLA3 2-4. The variant allele of PNPLA3 (148 isoleucine
to methionine protein variant; I148M) induces abnormal lipolysis and contributes to enhanced hepatic steatosis
as a result of chronic alcohol consumption, as well as more aggressive progression to inflammation and fibrosis
that are characteristic of the advanced stages of ALD2,4. We have already generated the human induced
pluripotent stem cell lines that will be used for this proposal, and we have optimized a protocol to differentiate
these stem cells to hepatocytes. We have performed basic characterization of PNPLA3 variant hepatocytes and
confirmed that they accumulate triglyceride-rich lipid droplets and express inflammatory cytokines that are
thought to be involved in progression from steatosis to hepatitis. To understand the mechanism by which the
variant PNPLA3 confers increased susceptibility to alcohol-related liver injury, we will perform detailed profiling
of lipid droplets of hepatocytes derived from human stem cell lines engineered to express the risk variant of
PNPLA3. We will determine the lipid composition, protein composition and profile of specific inflammatory
mediators that determine progression from steatosis to inflammation in ALD patients. We will use ethanol and
palmitic acid to mimic the environmental stress induced by alcohol consumption and lipotoxicity. Our main goal
is to identify novel therapeutic targets directly in live human hepatocytes that can be exploited for the treatment
of ALD.

## Key facts

- **NIH application ID:** 9979504
- **Project number:** 1R21AA027893-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Paulina M Ordonez Naranjo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $226,406
- **Award type:** 1
- **Project period:** 2020-04-10 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979504

## Citation

> US National Institutes of Health, RePORTER application 9979504, Progression from steatosis to steatohepatitis in alcoholic liver disease is enhanced by the risk allele of PNPLA3 via remodeling of lipid droplets and disruption of bioactive lipid composition (1R21AA027893-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979504. Licensed CC0.

---

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