Researchers identified genetic mutations that contribute to nonalcoholic fatty liver disease

This study lays the groundwork for the future development of approaches to activate the human Gm4951 homolog to combat NAFLD.

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Obesity and diabetes are well-known risk factors for nonalcoholic fatty liver disease (NAFLD), but the genetic factors contributing to the development of NAFLD remain poorly understood.

A new study by UT Southwestern researchers has identified an unknown cause of fatty liver disease absent obesity. Using a genetic screening platform, they demonstrated genetic mutations contributing to nonalcoholic fatty liver disease (NAFLD).

They found that a reduced Predicted gene 4951 (Gm4951) leads to nonalcoholic fatty liver disease absent obesity.

There are currently no recognized drugs or therapies for the condition, quickly becoming a significant contributor to chronic liver disease in the United States. Finding out how this gene contributes to the disease’s onset offers researchers looking for potential remedies a crucial new direction.

Lead author Zhao Zhang, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and the Division of Endocrinology in Internal Medicine, said, “We identified a rare non-obese mouse model of NAFLD caused by GM4951 deficiency. This study lays the groundwork for the future development of approaches to activate the human Gm4951 homolog to combat NAFLD.”

The genetic screening platform that researchers used allows researchers to screen for more than half of all genes in the mouse genome. It also enables the quick identification of mutations causing both quantitative and qualitative characteristics and the ability to identify mutations immediately.

Dr. Zhang said, “This study identified a potential human homolog of mouse GM4951 and the interaction of GM4951 with another human NAFLD/NASH associated protein HSD17B13, suggesting the discovery is likely conserved in humans.”

Using the screening platform, researchers were able to identify two semi-dominant allelic missense mutations (Oily and Carboniferous) of Gm4951. They also defined a crucial role for GTPase-mediated translocation in hepatic lipid metabolism.

Among their findings, the researchers found that loss of GM4951 causes NAFLD without obesity, that GM4951 promotes lipid oxidation to prevent lipid from accumulation in the liver and that GM4951 functions as a GTPase to translocate HSD17B13 to lipid droplets.

Dr. Zhang said“GM4951 is a poorly characterized protein, and this study defined the role of GM4951 as a GTPase involved in lipid oxidation. The GM4951-deficient mice developed nonalcoholic fatty liver disease on a high-fat diet with no changes in body weight or glucose metabolism.”

Journal Reference:

  1. Zhao Zhang et al., Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity, Nature Communications (2022). DOI: 10.1038/s41467-022-31812-4