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Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans

Xie, Baocai, Shi, Xiaochen, Li, Yan, Xia, Bo, Zhou, Jia, Du, Minjie, Xing, Xiangyang, Bai, Liang, Liu, Enqi, Alvarez, Fernando, Jin, Long, Deng, Shaoping, Mitchell, Grant A., Pan, Dengke, Li, Mingzhou, Wu, Jiangwei·2021·PLOS Genetics
DOI 10.1371/journal.pgen.1009891PMC PMC8584755
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Abstract

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.

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Crossref · 10.1371/journal.pgen.1009891

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  • Pigs lacking ASGR1 showed a decrease in non-HDL cholesterol in the circulation and a reduction in atherosclerotic lesions after a high-fat high-cholesterol diet, with no apparent liver damage.

    “Like in human carriers of ASGR1 inactivating mutations, pigs lacking ASGR1 showed a decrease in non-HDL cholesterol in the circulation and a reduction in atherosclerotic lesions after a high-fat high-cholesterol diet, with no apparent liver damage [85,86].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [85]

    The Results section on HFHC feeding reports lower non-HDL cholesterol and fewer atherosclerotic lesions in ASGR1-deficient pigs than in controls. But the Results section titled “Mild to moderate liver injury was observed in ASGR1-deficient pigs” reports hepatic inflammation and fibrosis, directly contradicting the claim of no apparent liver damage. The reported liver histology was from 24-month-old pigs on a normal diet, not the HFHC-fed cohort. (LLM, conf=0.88)

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  • ASGR1 regulates SREBP2-dependent signaling and expression of PCSK9, decreasing LDLR.

    “ASGR1 (Asialoglycoprotein receptor 1) Promotes LDLR internalization and degradation; Regulates SREBP2dependent signaling and expression of PCSK9 ↓ [84,85]”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [85]

    The Discussion (page unavailable) reports that ASGR1 deficiency increases hepatic LDLR protein and cites evidence that ASGR1 binds and degrades LDLR. It does not establish SREBP2-dependent signaling; instead, it excludes a PCSK9-mediated explanation for the LDLR change because plasma PCSK9 levels were comparable in ASGR1-deficient and control pigs. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • LDLR is targeted by ASGR1 in hepatocytes.

    “LDLR is targeted by ASGR1 in hepatocytes.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [147]

    The Discussion reports that ASGR1 binds and degrades LDLR, calling LDLR an endocytic target for ASGR1. It places that finding in HepG2 cells, however, and says whether it occurs in vivo remains to be investigated; the broader claim about hepatocytes is not established by this copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • ASGR1 functions to negatively regulate LDLR surface availability and LDL uptake.

    “suggesting that ASGR1 functions to negatively regulate LDLR surface availability and LDL uptake146,147.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [147]

    The Results report that ASGR1 deficiency increased hepatic LDLR protein and that ASGR1 knockdown increased LDL uptake in HepG2 cells, supporting a negative regulatory role. The paper does not establish the more specific claim about LDLR surface availability; its Discussion says whether ASGR1-mediated LDLR degradation occurs in vivo warrants further investigation. Page numbers are unavailable in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ASGR1 deficiency led to inhibition of HMG-CoA reductase, ultimately resulting in decreased de novo cholesterol synthesis and VLDL secretion.

    “ASGR1 deficiency led to the inhibition of HMG-CoA reductase (HMGCR), ultimately resulting in decreased de novo cholesterol synthesis and VLDL secretion.”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [85]

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Citations

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Metadata

Authors
Xie, B., Shi, X., Li, Y., Xia, B., Zhou, J., Du, M., Xing, X., Bai, L., Liu, E., Alvarez, F., Jin, L., Deng, S., Mitchell, G. A., Pan, D., Li, M., & Wu, J.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2021-11-11
Volume
17
Issue
11
Pages
e1009891
ISSN
1553-7404
DOI
10.1371/journal.pgen.1009891
PMC
PMC8584755
Cited by
46
References
8
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • the National Natural Science Foundation of China (32070602, U19A2036)
  • the special talent recruitment fund of northwest a&f university
  • the National Key Research & Development Program of China (2017YFC1103702)
  • the National Key R & D Program of China (2020YFA0509500)

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