Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1
Copyright © 2024 Elsevier Inc. All rights reserved..
Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Cell metabolism - 36(2024), 3 vom: 05. März, Seite 598-616.e9 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Kan [VerfasserIn] |
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| Links: |
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| Themen: |
2-methylbutyrylcarnitine |
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| Anmerkungen: |
Date Completed 08.03.2024 Date Revised 20.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.cmet.2024.01.014 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368915239 |
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| 245 | 1 | 0 | |a Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1 |
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| 520 | |a Copyright © 2024 Elsevier Inc. All rights reserved. | ||
| 520 | |a Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a 2-methylbutyrylcarnitine | |
| 650 | 4 | |a BTT 3033 | |
| 650 | 4 | |a gut microbial metabolite | |
| 650 | 4 | |a integrin α2β1 | |
| 650 | 4 | |a platelet hyperreactivity | |
| 650 | 4 | |a thrombosis | |
| 650 | 7 | |a Integrin alpha2beta1 |2 NLM | |
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| 700 | 1 | |a Huang, Bingding |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Yongxia |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Dongxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zefeng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yunchong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Na |e verfasserin |4 aut | |
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| 700 | 1 | |a Huang, Shuxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Pin |e verfasserin |4 aut | |
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| 700 | 1 | |a Zhou, Lifang |e verfasserin |4 aut | |
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| 700 | 1 | |a Liao, Baolin |e verfasserin |4 aut | |
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| 700 | 1 | |a Chen, Sifan |e verfasserin |4 aut | |
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