Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2022 Jul 16;13(1):4136. doi: 10.1038/s41467-022-31812-4.
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.
肥胖和糖尿病是众所周知的非酒精性脂肪性肝病（NAFLD）的危险因素，但导致 NAFLD 发展的遗传因素仍知之甚少。在这里，我们描述了从小鼠正向遗传筛选中鉴定出的预测基因 4951（Gm4951）的两个半显性等位基因突变（油性和石炭纪）。GM4951 缺陷型小鼠在高脂肪饮食（HFD）下发生 NAFLD，体重和葡萄糖代谢没有变化。此外，HFD 导致 Gm4951 水平降低，进而促进 NAFLD 的发展。GM4951 主要在肝细胞中表达，被验证为干扰素诱导的 GTPase。Gm4951 敲除小鼠的 NAFLD 与肝脏脂质氧化减少有关，肝脂质分泌无缺陷。在脂质负荷后，肝细胞 GM4951 易位到脂质滴（LDs），并随之带来羟甾体 17β-脱氢酶 13（HSD17B13），在没有 GM4951 的情况下，HSD17B13 不会发生这种易位。我们发现了一种由 GM4951 缺乏引起的罕见非肥胖型 NAFLD 小鼠模型，并确定了 GTPase 介导的易位在肝脂质代谢中的关键作用。
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