Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Aug 3, 2022Nature

Blocking ASGR1 lowers fat levels by increasing cholesterol removal

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Abstract

ASGR1 deficiency decreases lipid levels in serum and liver.

Loss-of-function variants in ASGR1 are linked to low cholesterol and reduced cardiovascular disease risk.
ASGR1 is found only in the liver and plays a role in breaking down certain blood proteins.
The deficiency of ASGR1 stabilizes LXRα, which helps transport cholesterol to high-density lipoprotein and facilitates its excretion.
AMPK, activated by ASGR1 deficiency, increases LXRα levels while decreasing SREBP1, which regulates fat production.
Anti-ASGR1 antibodies can lower lipid levels and work well with common cholesterol-lowering medications.

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High cholesterol is a major risk factor for cardiovascular disease. 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. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins. 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 faeces, 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. 1 2 3 4

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Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Abstract

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