Lack of VMP1 impairs hepatic lipoprotein secretion and promotes non-alcoholic steatohepatitis.
Lack of VMP1 impairs hepatic lipoprotein secretion and promotes non-alcoholic steatohepatitis.
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DOI：
10.1016/j.jhep.2022.04.010
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发表时间：
2022-09
影响因子：
25.7
通讯作者：
Ni, Hong-Min
中科院分区：
文献类型：
--
作者：
Jiang, Xiaoxiao;Fulte, Sam;Deng, Fengyan;Chen, Shiyuan;Xie, Yan;Chao, Xiaojuan;He, Xi C.;Zhang, Yuxia;Li, Tiangang;Li, Feng;McCoin, Colin;Morris, E. Matthew;Thyfault, John;Liu, Wanqing;Li, Linheng;Davidson, Nicholas O.;Ding, Wen-Xing;Ni, Hong-Min
胆固醇膜蛋白1（VMP 1）是一种内质网（ER）跨膜蛋白，其调节自噬体和脂滴的形成。最近的证据表明，VMP 1在斑马鱼和培养细胞的脂蛋白分泌中起着关键作用。然而，VMP 1在非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）中调节脂蛋白分泌和脂质蓄积的病理生理作用和机制尚不清楚。分别通过将Vmp 1flox或Vmp 1 KI小鼠与白蛋白-Cre小鼠杂交或通过注射AAV 8-TBG-cre产生肝脏特异性和肝细胞特异性Vmp 1敲除小鼠以及Vmp 1敲入小鼠。通过代谢组学和转录组学分析来表征这些小鼠中的脂质和能量代谢。还表征了喂食NASH饮食的具有VMP 1肝脏过表达的小鼠。Vmp 1的肝细胞特异性缺失严重损害VLDL分泌，导致大量肝脂肪变性、肝细胞死亡、炎症和纤维化，这些都是NASH的标志。从机制上讲，Vmp 1的丢失导致肝脏磷脂酰胆碱和磷脂酰乙醇胺水平降低以及磷脂组成的变化。小鼠肝脏中Vmp 1的缺失也导致ER双层中中性脂质的积累和线粒体β-氧化受损。在饮食诱导的NASH中，VMP 1的过表达通过改善VLDL分泌来改善脂肪变性。重要的是，我们还发现肝脏VMP 1的减少与人类的NAFLD/NASH相关。我们的研究结果提供了新的见解VMP 1在调节肝脏磷脂合成和脂蛋白分泌的NAFLD/NASH的发病机制的作用。非酒精性脂肪性肝病及其更严重的形式，非酒精性脂肪性肝炎，与肝脏中脂肪的积聚（脂肪变性）有关。然而，患者脂肪变性的确切机制尚未完全了解。在本文中，作者发现缺乏一种名为VMP 1的蛋白质会损害肝脏中脂肪的分泌和代谢，因此可能有助于非酒精性脂肪肝的发展和进展。
Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by which VMP1 regulates lipoprotein secretion and lipid accumulation in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are unknown. Liver-specific and hepatocyte-specific Vmp1 knockout mice as well as Vmp1 knock-in mice were generated by crossing Vmp1flox or Vmp1KI mice with albumin-Cre mice or by injecting AAV8-TBG-cre, respectively. Lipid and energy metabolism in these mice were characterized by metabolomic and transcriptome analyses. Mice with hepatic overexpression of VMP1 who were fed a NASH diet were also characterized. Hepatocyte-specific deletion of Vmp1 severely impaired VLDL secretion resulting in massive hepatic steatosis, hepatocyte death, inflammation and fibrosis, which are hallmarks of NASH. Mechanistically, loss of Vmp1 led to decreased hepatic levels of phosphatidylcholine and phosphatidylethanolamine as well as to changes in phospholipid composition. Deletion of Vmp1 in mouse liver also led to the accumulation of neutral lipids in the ER bilayer and impaired mitochondrial beta-oxidation. Overexpression of VMP1 ameliorated steatosis in diet-induced NASH by improving VLDL secretion. Importantly, we also showed that decreased liver VMP1 is associated with NAFLD/NASH in humans. Our results provide novel insights on the role of VMP1 in regulating hepatic phospholipid synthesis and lipoprotein secretion in the pathogenesis of NAFLD/NASH. Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis, are associated with a build-up of fat in the liver (steatosis). However, the exact mechanisms that underly steatosis in patients are not completely understood. Herein, the authors identified that the lack of a protein called VMP1 impairs the secretion and metabolism of fats in the liver and could therefore contribute to the development and progression of non-alcoholic fatty liver disease.
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DOI：
10.1083/jcb.202103105
发表时间：
2021-06-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li YE;Wang Y;Du X;Zhang T;Mak HY;Hancock SE;McEwen H;Pandzic E;Whan RM;Aw YC;Lukmantara IE;Yuan Y;Dong X;Don A;Turner N;Qi S;Yang H
通讯作者：
Yang H
影响因子：
7.7
作者：
Hashidate-Yoshida T;Harayama T;Hishikawa D;Morimoto R;Hamano F;Tokuoka SM;Eto M;Tamura-Nakano M;Yanobu-Takanashi R;Mukumoto Y;Kiyonari H;Okamura T;Kita Y;Shindou H;Shimizu T
通讯作者：
Shimizu T
影响因子：
64.8
作者：
Bard, F;Casano, L;Malhotra, V
通讯作者：
Malhotra, V
影响因子：
7.4
作者：
Ripatti, Pietari;Ramo, Joel T.;Ripatti, Samuli
通讯作者：
Ripatti, Samuli
影响因子：
4.8
作者：
Stone, SJ;Vance, JE
通讯作者：
Vance, JE