# ABHD5 and PNPLA3 in the development of fatty liver disease

> **NIH NIH F30** · WAYNE STATE UNIVERSITY · 2020 · $39,424

## Abstract

Project Abstract
Excessive fat accumulation in the liver can lead to liver failure and is a growing health concern. Hepatic
steatosis, the first stage of nonalcoholic fatty liver disease (NAFLD), has been reported in one out of every
three adults in the United States. Despite the clinical relevance of NAFLD, questions regarding its molecular
pathogenesis remain unanswered. A genome wide study for genes linked to NAFLD demonstrated that the
I148M variant of PNPLA3 is robustly associated with hepatic triglyceride (TG) content. However, the role of
PNPLA3 in the liver and the mechanism for how the I148M variant promotes liver fat accumulation remain
elusive. We have found PNPLA3 interacts with α/β hydrolase domain-containing 5 (ABHD5), the activator of
the main TG lipase found in the liver, adipose triglyceride lipase (ATGL; officially PNPLA2). This interaction is
dynamic and regulated by nutritional status. Furthermore, the I148M variant increases PNPLA3 affinity for
ABHD5. Our central hypothesis is that PNPLA3 interaction with ABHD5 suppresses lipolysis by
preventing the interaction of ABHD5 with ATGL/PNPLA2. In addition, we propose that the I148M
variant significantly increases affinity with ABHD5, leading to greater suppression of lipolysis and
greater liver fat accumulation. This proposal will examine the how PNPLA3 and the I148M variant affect the
subcellular trafficking of ABHD5 and ATGL. We will also determine the functional consequences of the
interaction of PNPLA3 and the I148M variant with ABHD5 in hepatocytes. The results of this proposal will lead
to a better understanding of how ABHD5 and PNPLA3 regulate lipid metabolism in the liver and how the I148M
variant disrupts this regulation leading to increased fat accumulation. Completion of this study will provide the
trainee with experience and tools needed to pursue a career as a physician-scientist.

## Key facts

- **NIH application ID:** 9857601
- **Project number:** 5F30DK116529-03
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Alexander C Yang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,424
- **Award type:** 5
- **Project period:** 2018-03-26 → 2023-03-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857601

## Citation

> US National Institutes of Health, RePORTER application 9857601, ABHD5 and PNPLA3 in the development of fatty liver disease (5F30DK116529-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857601. Licensed CC0.

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