Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.
Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.
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肝脏 SMLR1 的缺失会导致肝脂肪变性，并由于肝脏 VLDL 分泌减少而预防动脉粥样硬化。
DOI：
10.1002/hep.32709
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发表时间：
2023-11-01
期刊：
影响因子：
13.5
通讯作者：
Kuivenhoven, Jan Albert
中科院分区：
文献类型：
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作者：
van Zwol, Willemien;Rimbert, Antoine;Wolters, Justina C.;Smit, Marieke;Bloks, Vincent W.;Kloosterhuis, Niels J.;Huijkman, Nicolette C. A.;Koster, Mirjam H.;Tharehalli, Umesh;de Neck, Simon M.;Bournez, Colin;Fuh, Marceline M.;Kuipers, Jeroen;Rajan, Sujith;de Bruin, Alain;Ginsberg, Henry N.;van Westen, Gerard J. P.;Hussain, M. Mahmood;Scheja, Ludger;Heeren, Joerg;Zimmerman, Philip;van de Sluis, Bart;Kuivenhoven, Jan Albert
VLDL从肝脏的组装和分泌，影响肝脏和血浆脂质的途径，仍然不完全清楚。我们开始通过鉴定与MTTP基因共表达的基因来鉴定VLDL生物合成途径中的参与者，MTTP基因编码微粒体甘油三酯转移蛋白，该蛋白是载脂蛋白B（VLDL的核心蛋白）脂化的关键。使用人类和小鼠转录组数据集，我们鉴定了小亮氨酸富含蛋白1（SMLR 1），编码小亮氨酸富含蛋白1，一种功能未知的蛋白质，仅在肝脏和小肠中表达。为了评估SMLR 1在肝脏中的作用，我们使用体细胞CRISPR/CRISPR−相关蛋白9基因编辑来沉默肝细胞中的小鼠Smlr 1（Smlr 1 −LKO）。当喂食普通饲料时，雄性和雌性小鼠显示肝脂肪变性、血浆载脂蛋白B和甘油三酯减少以及VLDL分泌减少，但不影响微粒体甘油三酯转移蛋白活性。免疫荧光研究表明SMLR 1位于内质网和Cis−Golgi复合体中。雌性小鼠肝脏SMLR 1的缺失可防止饮食诱导的高脂血症和动脉粥样硬化，但会导致NASH。在高脂肪、高胆固醇饮食中，胰岛素和葡萄糖耐量试验并未显示雄性Smlr 1 −LKO小鼠与对照组之间存在差异。我们提出SMLR 1在VLDL从内质网到Cis-高尔基体复合体的运输中的作用。虽然这项研究揭示了SMLR 1在VLDL组装、运输和分泌途径中的作用，但它也表明NASH可以在葡萄糖稳态不受干扰和动脉粥样硬化保护的情况下发生。
The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co−expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine−rich protein 1 (SMLR1), encoding for small leucine−rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine. To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR−associated protein 9 gene editing to silence murine Smlr1 in hepatocytes (Smlr1−LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis−Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet−induced hyperlipidemia and atherosclerosis but causes NASH. On a high−fat, high−cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1−LKO mice versus controls. We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis−Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.
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DOI：
10.1074/jbc.ra120.015002
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Peng H;Chiu TY;Liang YJ;Lee CJ;Liu CS;Suen CS;Yen JJ;Chen HT;Hwang MJ;Hussain MM;Yang HC;Yang-Yen HF
通讯作者：
Yang-Yen HF
影响因子：
8
作者：
Boren, Jan;Adiels, Martin;Taskinen, Marja-Riitta
通讯作者：
Taskinen, Marja-Riitta
影响因子：
29
作者：
Li, Zhaoyu;Agellon, Luis B.;Vance, Dennis E.
通讯作者：
Vance, Dennis E.
影响因子：
25.7
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
通讯作者：
Ni, Hong-Min
影响因子：
4.4
作者：
Gordon SM;Li H;Zhu X;Shah AS;Lu LJ;Davidson WS
通讯作者：
Davidson WS