Ju-Qiong Wang ¹,  Liang-Liang Li ¹,  Ao Hu ¹,  Gang Deng ¹,  Jian Wei ¹,  Yun-Feng Li ¹,  Yuan-Bin Liu ¹,  Xiao-Yi Lu ¹,  Zhi-Ping Qiu ¹,  Xiong-Jie Shi ¹,  Xiaolu Zhao ¹,  Jie Luo ¹,  Bao-Liang Song ²

Affiliations

• 1College of Life Sciences, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China.
• 2College of Life Sciences, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China. blsong@whu.edu.cn.

PMID: 35922515   DOI: 10.1038/s41586-022-05006-3

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.