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モータータンパク質KIF13Bは代謝異常関連脂肪肝疾患を防ぐために肝代謝を調整する

  • 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*

サマリー

背景 キネシンファミリーメンバー13B（KIF13B）は重要なモータータンパク質であり、複数の細胞生物学的機能を果たしています。しかし、代謝異常関連脂肪肝疾患（MAFLD）におけるKIF13Bの意義はまだ明らかにされていません。本研究は、MAFLDにおけるKIF13Bの役割と基礎機構を調査し、潜在的な薬理学的標的として提案することを目的としています。方法 MAFLD患者および齧歯類モデルにおけるKIF13B発現を評価しました。全身性Kif13bノックアウトマウス、肝細胞特異的Kif13b欠損マウス、および異なる食餌を与えられたハムスターを用いて、脂質代謝およびMAFLDにおけるKif13bの役割を調査しました。さらに、Kif13bが肝臓の脂質恒常性およびMAFLD進行を制御する基礎機構をin vitroで検討しました。最後に、MAFLDの背景でのKif13bがアテローム性動脈硬化の発症に与える影響を調査しました。結果 MAFLD患者およびマウスモデルでKIF13Bの発現は低下していました。全身性または肝臓特異的なKif13b遺伝子ノックアウトを有する齧歯類は、自然発症性の肝脂肪症を示し、過栄養食によりさらに悪化しました。レンチウイルスによるヒトKIF13Bの過剰発現は、メチオニン-コリン欠乏食（MCD）を摂取したマウスにおいて代謝異常関連脂肪肝炎（MASH）を効果的に予防しました。さらに、Kif13b欠損はMAFLDの文脈で動脈硬化を促進しました。機序として、Kif13b欠損は肝臓の脂質合成を増加させ、ミトコンドリアの酸化的リン酸化を障害しました。追加のスクリーニングにより、Kif13bはAMP活性化型触媒サブユニットα1（AMPKα1）と相互作用し、AMPKα1のリン酸化を調節し、ミトコンドリアの恒常性を制御し、肝臓におけるステロール調節エレメント結合タンパク質1（Srebp1）を介した新規脂質合成を抑制することが明らかになりました。結論 本研究は、KIF13B欠損とMAFLDとの因果関係を確立し、KIF13BをMAFLD治療の潜在的な治療標的として強調しています。

キーワード

キネシンファミリーメンバー13B;AMP活性化型触媒サブユニットα1;ミトコンドリア恒常性;脂質代謝;代謝異常関連脂肪肝疾患

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