小柯机器人

抑制ASGR1可通过促进胆固醇排泄来降低脂质水平
2022-08-06 23:45
来源：小柯机器人

武汉大学宋保亮研究组发现，抑制ASGR1可通过促进胆固醇排泄来降低脂质水平。相关论文于2022年8月3日在线发表在《自然》杂志上。

研究人员发现，去唾液酸糖蛋白受体1（ASGR1）的缺失通过稳定LXRα而降低血清和肝脏中的脂质水平。LXRα上调ABCA1和ABCG5/G8，分别促进胆固醇向高密度脂蛋白的转运和向胆汁和粪便的排泄。ASGR1的缺乏阻碍了糖蛋白的内吞和溶酶体降解，降低了溶酶体中的氨基酸水平，从而抑制了mTORC1并激活了AMPK。一方面，AMPK通过减少LXRα的泛素连接酶BRCA1/BARD1而增加LXRα。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血脂水平，并与阿托伐他汀或依折麦布这两种广泛使用的低胆固醇血症药物显示出协同的有益作用。总之，这项研究表明，靶向ASGR1可以上调LXRα、ABCA1和ABCG5/G8，抑制SREBP1和脂肪生成，从而促进胆固醇排泄，降低血脂水平。
 
据悉，高胆固醇是心血管疾病的一个主要风险因素。目前，没有药物通过直接促进胆固醇的排泄来降低胆固醇。人类遗传学研究发现，功能缺失的ASGR1变体与低胆固醇和心血管疾病的风险降低有关。ASGR1只在肝脏中表达，并介导血液中阿西禄糖蛋白的内化和溶酶体降解。ASGR1影响胆固醇代谢的机制尚不清楚。
 
附：英文原文
 
Title: Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Author: Wang, Ju-Qiong, Li, Liang-Liang, Hu, Ao, Deng, Gang, Wei, Jian, Li, Yun-Feng, Liu, Yuan-Bin, Lu, Xiao-Yi, Qiu, Zhi-Ping, Shi, Xiong-Jie, Zhao, Xiaolu, Luo, Jie, Song, Bao-Liang

Issue&Volume: 2022-08-03

Abstract: High cholesterol is a major risk factor for cardiovascular disease1. 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 disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that 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 LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.

DOI: 10.1038/s41586-022-05006-3

Source: https://www.nature.com/articles/s41586-022-05006-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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