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.

高胆固醇是心血管疾病的主要危险因素¹。目前，没有药物通过直接促进胆固醇排泄来降低胆固醇。人类基因研究已确定功能丧失的亚洲糖蛋白受体 1 ( ASGR1 ) 变体与低胆固醇和心血管疾病风险降低相关²。ASGR1 仅在肝脏中表达并介导血液去唾液酸糖蛋白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Asgr1缺乏通过稳定 LXRα 降低血清和肝脏中的脂质水平。LXRα 上调 ABCA1 和 ABCG5/G8，从而促进胆固醇转运至高密度脂蛋白并排泄至胆汁和粪便⁴， 分别。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 通过减少其泛素连接酶 BRCA1/BARD1 来增加 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，并显示出与阿托伐他汀或依折麦布这两种广泛使用的降胆固醇药物的协同有益作用。总之，本研究表明，靶向 ASGR1 可上调 LXRα、ABCA1 和 ABCG5/G8，抑制 SREBP1 和脂肪生成，从而促进胆固醇排泄并降低血脂水平。