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Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion
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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“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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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
- Venue
- Nature
- Published
- 2022-08-03
- Volume
- 608
- Issue
- 7922
- Pages
- 413-420
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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