Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

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

doi:10.1038/s41586-022-05006-3

Cited by 190Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index.

Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

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·2022·Nature

DOI 10.1038/s41586-022-05006-3

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Abstract

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 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 4, 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.

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A study reported that Asgr1 deficiency in mice has no effect on hepatic LDLR abundance, and suggests that reduced plasma LDL-cholesterol in the absence of Asgr1 is due to increased LXRα signaling and enhanced reverse cholesterol efflux.
“However, this was recently contended by a study reporting Asgr1 deficiency in mice has no effect on hepatic LDLR abundance [88].Instead, this study suggests that reduced plasma LDL-cholesterol in the absence of Asgr1 is due to increased LXRα signaling and enhanced reverse cholesterol efflux.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [88]
The LDLR peptide has an N-terminal ligand binding domain with high affinity for Apolipoprotein E and Apolipoprotein B, the main structural components of VLDL/LDL.
“The LDLR peptide has an N-terminal ligand binding domain which has high affinity for Apolipoprotein E74,75, as well as Apolipoprotein B (ApoB)76, the main structural components of VLDL/LDL.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [75]
Glycosylation sites on LDLR not only impact LDLR stability and function but may also affect degradation rates of LDLR, specifically by ASGR1, an E3 ligase which recognizes a glycosylated region of LDLR.
“These glycosylation sites not only impact LDLR stability and function, but may also affect degradation rates of the LDLR, specifically by ASGR1 (discussed in more detail below), an E3 ligase which recognizes a glycosylated region of LDLR75.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [75]

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Inhibiting ASGR1 boosts cholesterol removal
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Targeting ASGR1 to lower cholesterol
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ASGR1 inhibition stimulates cholesterol excretion
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Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression
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Authors: Wang, J.-Q., Li, L.-L., Hu, A., Deng, G., Wei, J., Li, Y.-F., Liu, Y.-B., Lu, X.-Y., Qiu, Z.-P., Shi, X.-J., Zhao, X., Luo, J., & Song, B.-L.
Affiliations: Wuhan University (CN)
Corresponding author: Song, Bao-Liang
ORCID: Wang, Ju-Qiong
Li, Liang-Liang
Hu, Ao
Deng, Gang
Wei, Jian
Lu, Xiao-Yi
Shi, Xiong-Jie
Zhao, Xiaolu
Luo, Jie
Song, Bao-Liang
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2022-08-03
Volume: 608
Issue: 7922
Pages: 413-420
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-022-05006-3
OpenAlex: W4289638327
Semantic Scholar: 2c228e8e3bb08f6cb71f8c0237f1ccbab6eb5db0
Cited by: 188
References: 39
Citations by year: 2026: 51 · 2025: 53 · 2024: 45 · 2023: 31 · 2022: 7
FWCI: 14.70
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords: ASGR1, asialoglycoprotein receptor, cholesterol excretion, hypercholesterolemia, liver X receptor alpha, ABCA1, ABCG5/G8, SREBP1, lipogenesis, AMPK, mTORC1, lysosomal degradation, endocytosis, high-density lipoprotein, cardiovascular disease, neutralizing antibodies, ezetimibe, atorvastatin
MeSH terms: Atorvastatin, Ezetimibe, ATP Binding Cassette Transporter, Subfamily G, Member 5, ATP Binding Cassette Transporter, Subfamily G, Member 8, Liver X Receptors, Mechanistic Target of Rapamycin Complex 1, Asialoglycoproteins, Cardiovascular Diseases, Cholesterol, Drug Synergism, Endocytosis, Humans, Lipids, Liver, Lysosomes, BRCA1 Protein, Asialoglycoprotein Receptor, Ubiquitin-Protein Ligases, Lipid Metabolism, Sterol Regulatory Element Binding Protein 1, AMP-Activated Protein Kinases, ATP Binding Cassette Transporter 1

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Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

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