Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion
Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion
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抑制 ASGR1 通过促进胆固醇排泄来降低脂质水平
DOI：
10.1038/s41586-022-05006-3
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发表时间：
2022-08-03
期刊：
影响因子：
64.8
通讯作者：
Song, Bao-Liang
中科院分区：
文献类型：
--
作者：
Wang, Ju-Qiong;Li, Liang-Liang;Song, Bao-Liang
高胆固醇是心血管疾病的主要危险因素(1)。目前还没有一种药物通过直接促进胆固醇的排出来降低胆固醇。人类遗传学研究已经发现，功能缺失的亚洲糖蛋白受体1 （ASGR1）变异与低胆固醇和心血管疾病风险降低有关(2)。ASGR1仅在肝脏中表达，并介导血液中asialglyprotein的内化和溶酶体降解(3)。ASGR1影响胆固醇代谢的机制尚不清楚。在这里，我们发现Asgrl缺乏通过稳定LXR α降低血清和肝脏中的脂质水平。LXR α上调ABCA1和ABCG5/G8，分别促进胆固醇转运到高密度脂蛋白和排泄到胆汁和粪便中(4)。ASGR1缺乏阻断糖蛋白的内吞作用和溶酶体降解，降低溶酶体中的氨基酸水平，从而抑制mTORC1并激活AMPK。一方面，AMPK通过降低其泛素连接酶BRCA1/BARD1来增加LXRa。另一方面，AMPK抑制控制脂肪生成的srebp1。抗asgr1中和抗体通过增加胆固醇排泄来降低脂质水平，并与两种广泛使用的降胆固醇药物阿托伐他汀或依折替米贝显示协同有益作用。综上所述，本研究表明靶向ASGR1可上调LXR α、ABCA1和ABCG5/G8，抑制SREBP1和脂肪生成，从而促进胆固醇排泄，降低脂质水平。
High cholesterol is a major risk factor for cardiovascular disease(1). Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease(2). ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins(3). The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgrl deficiency decreases lipid levels in serum and liver by stabilizing LXR alpha. LXR alpha upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces(4), respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation ofglycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRa by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXR alpha, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.