Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity.
Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity.
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DOI：
10.1038/s41467-022-31812-4
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发表时间：
2022-07-16
影响因子：
16.6
通讯作者：
Beutler, Bruce
中科院分区：
文献类型：
--
作者：
Zhang, Zhao;Xun, Yu;Rong, Shunxing;Yan, Lijuan;SoRelle, Jeffrey A.;Li, Xiaohong;Tang, Miao;Keller, Katie;Ludwig, Sara;Moresco, Eva Marie Y.;Beutler, Bruce
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发展的遗传因素仍然知之甚少。在这里，我们描述了预测基因4951 （Gm4951）的两个半显性等位基因错义突变（油性和石炭纪），从小鼠的正向遗传筛选中鉴定出来。GM4951缺陷小鼠在高脂肪饮食（HFD）中发生NAFLD，体重或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，被证实是干扰素诱导的GTPase。Gm4951基因敲除小鼠的NAFLD与肝脏脂质氧化降低有关，肝脏脂质分泌无缺陷。脂质负载后，肝细胞GM4951易位到脂滴（ld），并携带羟基类固醇17β-脱氢酶13 (HSD17B13)，而在没有GM4951的情况下，该酶不会发生这种易位。我们鉴定了一种罕见的由GM4951缺乏引起的非肥胖小鼠NAFLD模型，并确定了gtpase介导的肝脏脂质代谢易位的关键作用。肥胖是脂肪肝的主要危险因素。在这里，使用正向遗传筛选，作者确定基因GM4951是参与小鼠脂质氧化和NAFLD发展的GTPase。
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. Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
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影响因子：
14.9
作者：
Mistry J;Chuguransky S;Williams L;Qureshi M;Salazar GA;Sonnhammer ELL;Tosatto SCE;Paladin L;Raj S;Richardson LJ;Finn RD;Bateman A
通讯作者：
Bateman A
影响因子：
6.7
作者：
Martens S;Parvanova I;Zerrahn J;Griffiths G;Schell G;Reichmann G;Howard JC
通讯作者：
Howard JC
DOI：
10.1002/hep.30350
发表时间：
2019-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ma Y;Belyaeva OV;Brown PM;Fujita K;Valles K;Karki S;de Boer YS;Koh C;Chen Y;Du X;Handelman SK;Chen V;Speliotes EK;Nestlerode C;Thomas E;Kleiner DE;Zmuda JM;Sanyal AJ;(for the Nonalcoholic Steatohepatitis Clinical Research Network);Kedishvili NY;Liang TJ;Rotman Y
通讯作者：
Rotman Y
DOI：
10.1007/978-1-59745-019-5_13
发表时间：
2010-01-01
期刊：
MOUSE CELL CULTURE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Li, Wan-Chun;Ralphs, Kate L.;Tosh, David
通讯作者：
Tosh, David
影响因子：
3.7
作者：
Zeng J;Parvanova IA;Howard JC
通讯作者：
Howard JC