Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression.
Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression.
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亚形 ASGR1 通过 INSIG1 介导的 SREBP 信号抑制调节脂质稳态
DOI：
10.1172/jci.insight.147038
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发表时间：
2021-10-08
期刊：
影响因子：
8
通讯作者：
Li YX
中科院分区：
文献类型：
--
作者：
Xu Y;Tao J;Yu X;Wu Y;Chen Y;You K;Zhang J;Getachew A;Pan T;Zhuang Y;Yuan F;Yang F;Lin X;Li YX
一项群体遗传学研究发现，脱唾液酸糖蛋白受体1（ASGR 1）突变携带者的非HDL-胆固醇（非HDL-c）水平显著降低，心血管疾病的风险降低。然而，这一现象背后的机制仍不清楚。在这里，我们建立了Asgr 1基因敲除小鼠，代表了一个血脂谱显着降低非HDL-C和甘油三酯（TG）引起的分泌减少和VLDL/LDL的摄取增加。这两种表型与微粒体甘油三酯转移蛋白和前蛋白转化酶枯草杆菌蛋白酶/kexin 9型的表达降低有关，这两种基因是固醇调节元件结合蛋白（SREBPs）的关键靶基因。此外，有较少的核SREBP（nSREBP），由于更多的SREBP被困在内质网中，这是由胰岛素诱导基因1（INSIG 1），SREBP的锚的表达增加引起的。在不同的模型中，进行过表达和基因敲减干预以挽救ASGR 1缺陷表型，我们发现INSIG 1敲减独立地逆转了ASGR 1突变表型，血清总胆固醇，LDL-c，TG和肝脏胆固醇含量增加，伴随着SREBP信号的恢复。ASGR 1拯救实验减少了INSIG 1，并恢复了SREBP网络缺陷，表现为载脂蛋白B分泌改善和LDL摄取减少。我们的观察结果表明，增加INSIG 1是一个关键因素，负责ASGR 1缺乏相关的血脂变化和nSREBP抑制。ASGR 1/INSIG 1/SREBP轴调节脂质止血的这一发现可能为降脂药物开发提供多个潜在靶点。
A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had substantially lower non–HDL-cholesterol (non–HDL-c) levels and reduced risks of cardiovascular diseases. However, the mechanism behind this phenomenon remained unclear. Here, we established Asgr1-knockout mice that represented a plasma lipid profile with significantly lower non–HDL-c and triglyceride (TG) caused by decreased secretion and increased uptake of VLDL/LDL. These 2 phenotypes were linked with the decreased expression of microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9, 2 key targeted genes of sterol regulatory element–binding proteins (SREBPs). Furthermore, there were fewer nuclear SREBPs (nSREBPs) on account of more SREBPs being trapped in endoplasmic reticulum, which was caused by an increased expression of insulin-induced gene 1 (INSIG1), an anchor of SREBPs. Overexpression and gene knockdown interventions, in different models, were conducted to rescue the ASGR1-deficient phenotypes, and we found that INSIG1 knockdown independently reversed the ASGR1-mutated phenotypes with increased serum total cholesterol, LDL-c, TG, and liver cholesterol content accompanied by restored SREBP signaling. ASGR1 rescue experiments reduced INSIG1 and restored the SREBP network defect as manifested by improved apolipoprotein B secretion and reduced LDL uptake. Our observation demonstrated that increased INSIG1 is a critical factor responsible for ASGR1 deficiency–associated lipid profile changes and nSREBP suppression. This finding of an ASGR1/INSIG1/SREBP axis regulating lipid hemostasis may provide multiple potential targets for lipid-lowering drug development.
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影响因子：
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作者：
Rubin, Diana;Schneider-Muntau, Alexandra;Doering, Frank
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DOI：
10.1161/atvbaha.108.179564
发表时间：
2009-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
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作者：
Goldstein JL;Brown MS
通讯作者：
Brown MS