TY - JOUR
T1 - Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
AU - Zhang, Zhao
AU - Xun, Yu
AU - Rong, Shunxing
AU - Yan, Lijuan
AU - SoRelle, Jeffrey A.
AU - Li, Xiaohong
AU - Tang, Miao
AU - Keller, Katie
AU - Ludwig, Sara
AU - Moresco, Eva Marie Y.
AU - Beutler, Bruce
N1 - Funding Information:
We thank the Histo Pathology, Mass Spectrometry, Live Cell Imaging, and Metabolic Phenotyping Cores of the University of Texas Southwestern Medical Center for providing excellent services. We thank Dr. Helen Hobbs at the University of Texas Southwestern Medical Center for providing HSD17B13 antibodies and helpful discussions, Dr. Jay Horton at the University of Texas Southwestern Medical Center for helping with lipid oxidation experiments. This work was supported by National Institutes of Health grants R00 DK115766 (Z.Z.), R01 DK130959 (Z.Z.), R01 AI125581 (B.B.), and U19 AI100627 (B.B.), and by the Lyda Hill foundation (B.B.). This work was also supported in part by a sponsored research agreement from Pfizer, Inc.
Funding Information:
We thank the Histo Pathology, Mass Spectrometry, Live Cell Imaging, and Metabolic Phenotyping Cores of the University of Texas Southwestern Medical Center for providing excellent services. We thank Dr. Helen Hobbs at the University of Texas Southwestern Medical Center for providing HSD17B13 antibodies and helpful discussions, Dr. Jay Horton at the University of Texas Southwestern Medical Center for helping with lipid oxidation experiments. This work was supported by National Institutes of Health grants R00 DK115766 (Z.Z.), R01 DK130959 (Z.Z.), R01 AI125581 (B.B.), and U19 AI100627 (B.B.), and by the Lyda Hill foundation (B.B.). This work was also supported in part by a sponsored research agreement from Pfizer, Inc.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-31812-4
DO - 10.1038/s41467-022-31812-4
M3 - Article
C2 - 35842425
AN - SCOPUS:85134219346
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4136
ER -