# The Role of Gm4951 in Nonalcoholic Fatty Liver Disease

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $360,800

## Abstract

PROJECT SUMMARY
 Nonalcoholic fatty liver disease (NAFLD) is becoming a global human health problem. Our long-term goal is
to understand molecular mechanisms of NAFLD, and to translate this knowledge into novel therapeutic strategies.
Due to the physiologic similarities between humans and mice, and the propensity of mice to develop a disease
closely mimicking NAFLD when fed a high fat diet (HFD), mice have provided us with fundamental insights into
NAFLD pathogenesis. In humans and mice, genetic variation influences the rate and severity of hepatosteatosis
under a given set of environmental conditions. To identify genes that influence the process, we utilized unbiased
forward genetic screening and highly automated meiotic mapping to identify mutations that cause NAFLD in mice
sensitized by a HFD. Two semi-dominant missense alleles of predicted gene 4951 (Gm4951), named Oily and
Carboniferous, were detected in this screen. As distinct from most NAFLD mutants that are associated with
obesity, our preliminary data showed that Gm4951 deficient mice had dramatically increased hepatic lipid
accumulation without a concomitant increase of body weight on a HFD. Gm4951 was highly expressed in
hepatocytes. Knockout of Gm4951 increased lipid content and overexpression of Gm4951 decreased lipid
content of primary hepatocytes in vitro, suggesting hepatocyte-intrinsic regulation of lipid content. Gm4951
knockout livers showed decreased expression of lipid oxidation genes. Mass spectrometry analysis of
endogenous GM4951 interacting proteins revealed interaction with lipid droplet protein Hydroxysteroid 17β-
dehydrogenase 13 (HSD17B13) and lipid oxidation enzymes. Moreover, the transcription of Gm4951 in
hepatocytes was activated by interferon gamma (IFN-γ), which effectively decreased lipid content, much as when
GM4951 was overexpressed. These results led to our central hypothesis that GM4951 is critical for promoting
lipid oxidation, and limits hepatic lipid accumulation. To test this hypothesis, we propose to pursue three Specific
Aims. Aim 1 will further investigate the development of NAFLD in GM4951 deficient mice. Aim 2 will determine
the precise mechanistic role of GM4951 in regulating lipid metabolism. Aim 3 will study the transcriptional
regulation of Gm4951, including the liver-specific expression pattern and the inducible expression by IFN-γ.
Understanding how to activate GM4951 and what’s the human homolog of GM4951 would offer approaches to
preventing or treating NAFLD. These will be studied in Aim 3 as well. The NAFLD phenotype caused by GM4951
deficiency is fundamentally distinct from the classic obesity-associated NAFLD mouse models. GM4951 is
specifically expressed in the liver and operates there to limit lipid accumulation. Thus, finding ways to activate
GM4951 will provide a new means of reducing hepatic lipid content. Completion of the proposed work will
suggest new therapeutic targets to combat NAFLD.

## Key facts

- **NIH application ID:** 10339213
- **Project number:** 1R01DK130959-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Zhao Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,800
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339213

## Citation

> US National Institutes of Health, RePORTER application 10339213, The Role of Gm4951 in Nonalcoholic Fatty Liver Disease (1R01DK130959-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10339213. Licensed CC0.

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