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A proteína motora KIF13B orquestra o metabolismo hepático para prevenir a doença hepática gordurosa associada à disfunção metabólica

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

    Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China

Guo-Lin Miao12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Wen-Xi Zhang1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Yi-Tong Xu1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Biomedical Informatics, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Yi-Ran Liu3,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Ping-Ping Lai1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Jia-Bao Guo1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Gong-Lie Chen1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Jing-Xuan Chen1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Zi-Hao Zhou1,  
  • Affiliation：

    Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110134, China

Yan-Wei Li4,  
  • Affiliation：

    Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110134, China

Chong Zhang4,  
  • Affiliation：

    Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110134, China

Yang Ding4,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Lian-Xin Zhang1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Yu-Fei Han1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Jin-Xuan Chen1,  
  • Affiliation：

    State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education, Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China

Jing-Dong Wu5,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Yin-Qi Zhao1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Si Mei1,  
  • Affiliation：

    State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education, Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China

Yang Zhao5,  
  • Affiliation：

    Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China

Yuan-Wu Ma6,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Ling Zhang1,  
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

Wei Huang1,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Biomedical Informatics, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

  • Email：zhaodongyu@bjmu.edu.cn
  • Introduction：* Dong-Yu Zhao zhaodongyu@bjmu.edu.cn
Dong-Yu Zhao3*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

    Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China

    Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266113, Shandong, China

  • Email：donged@bjmu.edu.cn
  • Introduction：Er-Dan Dong donged@bjmu.edu.cn
Er-Dan Dong127*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

  • Email：wangyuhui2009@bjmu.edu.cn
  • Introduction：Yu-Hui Wang wangyuhui2009@bjmu.edu.cn
Yu-Hui Wang1*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China

    Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing 100191, China

  • Email：xianxunde@bjmu.edu.cn
  • Introduction：Xun-De Xian xianxunde@bjmu.edu.cn
Xun-De Xian18*

Resumo

Contexto O membro 13B da família da quinesina (KIF13B), uma proteína motora crucial, exerce múltiplas funções biológicas celulares. No entanto, a implicação do KIF13B na doença hepática gordurosa associada à disfunção metabólica (MAFLD) ainda não foi explorada. Este estudo teve como objetivo investigar o papel do KIF13B e o mecanismo subjacente na MAFLD, propondo-o como um alvo farmacológico potencial. Métodos Avaliamos a expressão do KIF13B em pacientes com MAFLD e modelos de roedores. Os papéis do Kif13b no metabolismo lipídico e na MAFLD foram investigados usando camundongos knockout totais para Kif13b, camundongos com deficiência específica em hepatócitos para Kif13b e hamsters expostos a dietas diferentes. Os mecanismos subjacentes pelos quais o Kif13b regula a homeostase lipídica hepática e a progressão da MAFLD foram explorados in vitro. Finalmente, o impacto do Kif13b no desenvolvimento da aterosclerose foi estudado no contexto da MAFLD. Resultados A expressão do KIF13B foi reduzida em pacientes e modelos murinos com MAFLD. Roedores com knockout global ou específico do gene Kif13b no fígado exibem esteatose hepática espontânea, que é agravada por diferentes dietas de supernutrição. A superexpressão do KIF13B humano por lentivírus preveniu efetivamente a esteato-hepatite associada a disfunção metabólica (MASH) em camundongos alimentados com dieta deficiente em metionina-colina (MCD). Além disso, a deficiência de Kif13b acelera a aterosclerose no contexto da MAFLD. Mecanicamente, a depleção de Kif13b aumenta a síntese lipídica hepática e prejudica a fosforilação oxidativa mitocondrial. A triagem adicional revela que Kif13b interage com a subunidade catalítica alfa 1 ativada por AMP (AMPKα1) para regular a fosforilação de AMPKα1, governando a homeostase mitocondrial e suprimindo a lipogênese de novo mediada pela proteína de ligação ao elemento regulador de esteróis 1 (Srebp1) no fígado. Conclusão Este trabalho estabelece uma relação causal entre a deficiência de KIF13B e MAFLD, enfatizando KIF13B como um alvo terapêutico potencial para o tratamento da MAFLD.

Palavras-chave

Membro da família da quinesina 13B;Subunidade catalítica alfa 1 ativada por AMP;Homeostase mitocondrial;Metabolismo lipídico;Doença hepática gordurosa associada à disfunção metabólica

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