Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity

Zhao Zhang (), Yu Xun, Shunxing Rong, Lijuan Yan, Jeffrey A. SoRelle, Xiaohong Li, Miao Tang, Katie Keller, Sara Ludwig, Eva Marie Y. Moresco and Bruce Beutler ()
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Zhao Zhang: University of Texas Southwestern Medical Center
Yu Xun: University of Texas Southwestern Medical Center
Shunxing Rong: University of Texas Southwestern Medical Center
Lijuan Yan: University of Texas Southwestern Medical Center
Jeffrey A. SoRelle: University of Texas Southwestern Medical Center
Xiaohong Li: University of Texas Southwestern Medical Center
Miao Tang: University of Texas Southwestern Medical Center
Katie Keller: University of Texas Southwestern Medical Center
Sara Ludwig: University of Texas Southwestern Medical Center
Eva Marie Y. Moresco: University of Texas Southwestern Medical Center
Bruce Beutler: University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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. Here we describe two semi-dominant allelic missense mutations (Oily and Carboniferous) of Predicted gene 4951 (Gm4951) identified from a forward genetic screen in mice. GM4951 deficient mice developed NAFLD on high fat diet (HFD) with no changes in body weight or glucose metabolism. Moreover, HFD caused a reduction in the level of Gm4951, which in turn promoted the development of NAFLD. Predominantly expressed in hepatocytes, GM4951 was verified as an interferon inducible GTPase. The NAFLD in Gm4951 knockout mice was associated with decreased lipid oxidation in the liver and no defect in hepatic lipid secretion. After lipid loading, hepatocyte GM4951 translocated to lipid droplets (LDs), bringing with it hydroxysteroid 17β-dehydrogenase 13 (HSD17B13), which in the absence of GM4951 did not undergo this translocation. We identified a rare non-obese mouse model of NAFLD caused by GM4951 deficiency and define a critical role for GTPase-mediated translocation in hepatic lipid metabolism.

Date: 2022
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DOI: 10.1038/s41467-022-31812-4

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