2. Academic Validation
  3. Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1

  • Cell Metab. 2024 Mar 5;36(3):598-616.e9. doi: 10.1016/j.cmet.2024.01.014.
Kan Huang 1,  Zilun Li 2,  Xi He 3,  Jun Dai 4,  Bingding Huang 5,  Yongxia Shi 4,  Dongxiao Fan 2,  Zefeng Zhang 6,  Yunchong Liu 2,  Na Li 2,  Zhongyu Zhang 6,  Jiangyun Peng 6,  Chenshu Liu 2,  Renli Zeng 6,  Zhipeng Cen 6,  Tengyao Wang 6,  Wenchao Yang 2,  Meifeng Cen 7,  Jingyu Li 5,  Shuai Yuan 4,  Lu Zhang 4,  Dandan Hu 4,  Shuxiang Huang 4,  Pin Chen 8,  Peilong Lai 9,  Liyan Lin 6,  Jielu Wen 6,  Zhengde Zhao 2,  Xiuyi Huang 2,  Lining Yuan 6,  Lifang Zhou 6,  Haoliang Wu 2,  Lihua Huang 6,  Kai Feng 3,  Jian Wang 3,  Baolin Liao 3,  Weiping Cai 3,  Xilong Deng 3,  Yueping Li 3,  Jianping Li 3,  Zhongwei Hu 3,  Li Yang 3,  Jiaojiao Li 3,  Youguang Zhuo 3,  Fuchun Zhang 3,  Lin Lin 10,  Yifeng Luo 11,  Wei Zhang 12,  Qianlin Ni 12,  Xiqiang Hong 12,  Guangqi Chang 2,  Yang Zhang 13,  Dongxian Guan 14,  Weikang Cai 15,  Yutong Lu 8,  Fang Li 16,  Li Yan 17,  Meng Ren 18,  Linghua Li 19,  Sifan Chen 20
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 2 Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 3 Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China.
  • 4 Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China.
  • 5 College of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong 518118, China.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China.
  • 7 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
  • 8 National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
  • 9 Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
  • 10 Department of Respiratory Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
  • 11 Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 12 Wuhan Metware Biotechnology Co., Ltd., Wuhan, Hubei 430070, China.
  • 13 School of Public Health, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China.
  • 14 Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 15 Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
  • 16 Department of Obstetrics and Gynecology, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510620, China.
  • 17 Guangdong Clinical Research Center for Metabolic Diseases (Diabetes), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
  • 18 Guangdong Clinical Research Center for Metabolic Diseases (Diabetes), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China. Electronic address: renmeng80@139.com.
  • 19 Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China. Electronic address: llheliza@126.com.
  • 20 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China. Electronic address: chensf26@mail.sysu.edu.cn.
PMID: 38401546 DOI: 10.1016/j.cmet.2024.01.014
Abstract

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.

Keywords

2-methylbutyrylcarnitine; BTT 3033; gut microbial metabolite; integrin α2β1; platelet hyperreactivity; thrombosis.

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