# Role of Hepatic GDPD3 in Mechanisms of Lipid Metabolism

> **NIH NIH K01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $116,424

## Abstract

PROJECT SUMMARY/ABSTRACT
Nonalcoholic fatty liver disease (NAFLD), affecting ~30% of the U.S. population, is projected to replace
hepatitis C as the leading cause of liver transplantation by 2020. Developing effective NAFLD treatments is
hampered by a poor understanding of its underlying mechanisms, including complex interactions between
genetic and environmental factors. Glycerophosphodiester phosphodiesterase domain-containing protein 3
(GDPD3) is a newly discovered enzyme containing lysophospholipase D activity that converts lysophospholipid
to lysophosphatidic acid (lysoPA) in non-hepatic cells. Mammalian GDPD3 has not previously been implicated
in hepatic lipid metabolism. Our preliminary data indicates a positive correlation between human GDPD3
expression and triglyceride (TG) accumulation in hepatocytes and mouse livers, suggesting a novel gene in the
regulation of hepatic TG homeostasis. Nonetheless, the intracellular locations, substrate specificity,
physiological function, and molecular mechanisms of human GDPD3 in hepatocytes/livers are unknown.
Therefore, in this study, with the guidance of a highly experienced multi-disciplinary mentoring group, we
propose to investigate enzymatic properties of human GDPD3 and explore whether human GDPD3 is a causal
gene for hepatic steatosis. More specifically, we are asking three questions: 1) Is human GDPD3 an
endoplasmic reticulum membrane-associated enzyme containing lysophospholipase D activity? 2) Does
human GDPD3 increase lysoPA production resulting in increased hepatic TG synthesis and accumulation via
the glycerol phosphate pathway? 3) Does human GDPD3-produced lysoPA activate peroxisome proliferator-
activated receptor gamma (PPARγ) which enhances hepatic steatosis via increased fatty acid (FA) uptake and
TG synthesis? To answer these questions, we will overexpress human GDPD3 in hepatoma cell lines and in
mouse liver to determine: a) the effect of human GDPD3 overexpression on oleic acid-induced TG
accumulation in hepatoma cells and diet-induced hepatic steatosis in mice; b) the subcellular localization of
human GDPD3 in hepatoma cells and mouse primary hepatocytes; and c) the amount and molecular species
of GDPD3 lipid substrates and products in mouse livers. Liver-specific human GDPD3 overexpressing mice
with loss-of-function or gain-of-function in PPARγ will be fed chow or a Western-type diet to induce hepatic
steatosis. We will perform comprehensive hepatic and systemic metabolic phenotyping on these mice. Primary
hepatocytes will be used to investigate de novo lipogenesis, FA uptake and incorporation into TG, FA
oxidation, and very low density lipoprotein-TG secretion using radioactive isotopes. When the proposed aims
are achieved, we will have a better mechanistic understanding of the relationship between human GDPD3 and
hepatic steatosis, to address the gap in knowledge regarding NAFLD pathogenesis and inform strategies for its
treatment. Finally, this proposal provides the necessa...

## Key facts

- **NIH application ID:** 10242757
- **Project number:** 5K01DK117069-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Chia-Chi Chuang Key
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $116,424
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242757

## Citation

> US National Institutes of Health, RePORTER application 10242757, Role of Hepatic GDPD3 in Mechanisms of Lipid Metabolism (5K01DK117069-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10242757. Licensed CC0.

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