ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice
Abstract Abstract The asialoglycoprotein receptor 1 (ASGR1), a multivalent carbohydrate-binding receptor that primarily is responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues, has been implic...
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| Format: | Article |
| Language: | English |
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BMC
2024-11-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | https://doi.org/10.1186/s12933-024-02507-5 |
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| author | Monika Svecla Annalisa Moregola Lorenzo Da Dalt Jasmine Nour Andrea Baragetti Patrizia Uboldi Alessandra Idini Manfred Wuhrer Giangiacomo Beretta David Falck Fabrizia Bonacina Giuseppe Danilo Norata |
| author_facet | Monika Svecla Annalisa Moregola Lorenzo Da Dalt Jasmine Nour Andrea Baragetti Patrizia Uboldi Alessandra Idini Manfred Wuhrer Giangiacomo Beretta David Falck Fabrizia Bonacina Giuseppe Danilo Norata |
| author_sort | Monika Svecla |
| collection | DOAJ |
| description | Abstract Abstract The asialoglycoprotein receptor 1 (ASGR1), a multivalent carbohydrate-binding receptor that primarily is responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues, has been implicated in modulating the lipid metabolism and reducing cardiovascular disease burden. In this study, we investigated the impact of ASGR1 deficiency (ASGR1−/−) on atherosclerosis by evaluating its effects on plaque formation, lipid metabolism, circulating immunoinflammatory response, and circulating N-glycome under the hypercholesterolemic condition in ApoE-deficient mice. After 16 weeks of a western-type diet, ApoE−/−/ASGR1−/− mice presented lower plasma cholesterol and triglyceride levels compared to ApoE−/−. This was associated with reduced atherosclerotic plaque area and necrotic core formation. Interestingly, ApoE−/−/ASGR1−/− mice showed increased levels of circulating immune cells, increased AST/ALT ratio, and no changes in the N-glycome profile and liver morphology. The liver of ApoE−/−/ASGR1−/− mice, however, presented alterations in the metabolism of lipids, xenobiotics, and bile secretion, indicating broader alterations in liver homeostasis beyond lipids. These data suggest that improvements in circulating lipid metabolism and atherosclerosis in ASGR1 deficiency is paralleled by a deterioration of liver injury. These findings point to the need for additional evaluation before considering ASGR1 as a pharmacological target for dyslipidemia and cardiovascular disorders. Graphical abstract |
| format | Article |
| id | doaj-art-22aa1926ab7d4d789f5776e7cae7fd1e |
| institution | DOAJ |
| issn | 1475-2840 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj-art-22aa1926ab7d4d789f5776e7cae7fd1e2025-08-20T02:51:48ZengBMCCardiovascular Diabetology1475-28402024-11-0123111410.1186/s12933-024-02507-5ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- miceMonika Svecla0Annalisa Moregola1Lorenzo Da Dalt2Jasmine Nour3Andrea Baragetti4Patrizia Uboldi5Alessandra Idini6Manfred Wuhrer7Giangiacomo Beretta8David Falck9Fabrizia Bonacina10Giuseppe Danilo Norata11Department of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoCenter for Proteomics and Metabolomics, Leiden University Medical CenterDepartment of Environmental Science and Policy, Università degli Studi di MilanoCenter for Proteomics and Metabolomics, Leiden University Medical CenterDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di MilanoAbstract Abstract The asialoglycoprotein receptor 1 (ASGR1), a multivalent carbohydrate-binding receptor that primarily is responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues, has been implicated in modulating the lipid metabolism and reducing cardiovascular disease burden. In this study, we investigated the impact of ASGR1 deficiency (ASGR1−/−) on atherosclerosis by evaluating its effects on plaque formation, lipid metabolism, circulating immunoinflammatory response, and circulating N-glycome under the hypercholesterolemic condition in ApoE-deficient mice. After 16 weeks of a western-type diet, ApoE−/−/ASGR1−/− mice presented lower plasma cholesterol and triglyceride levels compared to ApoE−/−. This was associated with reduced atherosclerotic plaque area and necrotic core formation. Interestingly, ApoE−/−/ASGR1−/− mice showed increased levels of circulating immune cells, increased AST/ALT ratio, and no changes in the N-glycome profile and liver morphology. The liver of ApoE−/−/ASGR1−/− mice, however, presented alterations in the metabolism of lipids, xenobiotics, and bile secretion, indicating broader alterations in liver homeostasis beyond lipids. These data suggest that improvements in circulating lipid metabolism and atherosclerosis in ASGR1 deficiency is paralleled by a deterioration of liver injury. These findings point to the need for additional evaluation before considering ASGR1 as a pharmacological target for dyslipidemia and cardiovascular disorders. Graphical abstracthttps://doi.org/10.1186/s12933-024-02507-5AtherosclerosisAsialoglycoprotein receptor 1CholesterolPlaque compositionLiver metabolism |
| spellingShingle | Monika Svecla Annalisa Moregola Lorenzo Da Dalt Jasmine Nour Andrea Baragetti Patrizia Uboldi Alessandra Idini Manfred Wuhrer Giangiacomo Beretta David Falck Fabrizia Bonacina Giuseppe Danilo Norata ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice Cardiovascular Diabetology Atherosclerosis Asialoglycoprotein receptor 1 Cholesterol Plaque composition Liver metabolism |
| title | ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice |
| title_full | ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice |
| title_fullStr | ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice |
| title_full_unstemmed | ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice |
| title_short | ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice |
| title_sort | asgr1 deficiency improves atherosclerosis but alters liver metabolism in apoe mice |
| topic | Atherosclerosis Asialoglycoprotein receptor 1 Cholesterol Plaque composition Liver metabolism |
| url | https://doi.org/10.1186/s12933-024-02507-5 |
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