Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

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.

Automated summary

This study demonstrates that targeting ASGR1 can lower lipid levels in the blood and liver through various mechanisms, including increasing the expression of LXRα and ABCA1, ABCG5/G8, inhibiting SREBP1 and lipogenesis, and promoting cholesterol excretion.