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Pyruvate kinase M2 (PKM2) tetramerization protects against hepatic stellate cell activation and liver fibrosis.

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收录情况： ◇ SCIE

作者：
Zheng Dandan[1] * ; Jiang Yuchuan[1] * ; Qu Chen[1] ; Yuan Hui[1] ; Hu Kaishun[2] ; He Lu[1] ; Chen Peng[1] ; Li Jinying[3] ; Tu Mengxian[1] ; Lin Lehang[2] ; Chen Hengxing[2] ; Lin Zelong[1] ; Lin Wenyu[4] ; Fan Jun[5] ; Cheng Guohua[6] ; Hong Jian[1,7,*1] ;
机构： [1]Department of Abdominal Surgery,Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China [2]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China [3]Department of Gastroenterology,the First Affiliated Hospital of Jinan University, Guangzhou, China [4]Gastrointestinal Unit,Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts [5]Department of Medical Biochemistry and Molecular Biology,College of Pharmacy, Jinan University, Guangzhou, China [6]Department of Pathophysiology,College of Pharmacy, Jinan University, Guangzhou, China [7]School of Medicine, and the Department of Pharmacy,College of Pharmacy, Jinan University, Guangzhou, China
出处：
DOI： 10.1016/j.ajpath.2020.08.002
ISSN：

摘要：
Liver fibrosis is an increasing health problem worldwide, for which no effective anti-fibrosis drugs are available. Although the involvement of aerobic glycolysis in hepatic stellate cells (HSCs) activation has been reported, the role of PKM2 in liver fibrogenesis still remains unknown. We examined PKM2 expression and location in liver tissues and primary hepatic cells. The in vitro and in vivo effects of a PKM2 antagonist (shikonin) and its allosteric agent (TEPP-46) on liver fibrosis were investigated in HSCs and liver fibrosis mouse model. Chromatin immunoprecipitation sequencing (ChIP) and immunoprecipitation were performed to identify the relevant molecular mechanisms. We found that PKM2 expression was significantly upregulated in both mouse and human fibrotic livers compared to normal livers, and mainly detected in activated, rather than quiescent HSCs. PKM2 knockdown markedly inhibited the activation and proliferation of HSCs in vitro. Interestingly, we found that the PKM2 dimer, rather than the tetramer, induced HSC activation. PKM2 tetramerization induced by TEPP-46 effectively inhibited HSC activation, reduced aerobic glycolysis, and decreased MYC and CCND1 expression via regulating histone H3K9 acetylation in activated HSCs. TEPP-46 and shikonin dramatically attenuated liver fibrosis in vivo. Our findings demonstrate a non-metabolic role of PKM2 in liver fibrosis. PKM2 tetramerization or suppression could prevent HSC activation and protects against liver fibrosis. Copyright © 2020. Published by Elsevier Inc.

基金：
Supported by National Natural Science Foundation of China grants 81672320 (J.H.), 81871987 (J.H.), 81802423 (C.Q.), and 81772821 (K.H.); Science and Technology Program of Guangzhou, China, grant 201704020128 (J.H.); Municipal University Science and Technology Program of Guangzhou Education Bureau grant 1201410075 (J.H.); Fundamental Research Funds for the Central Universities grant 21620106 (J.H.); Yangcheng Scholar Program grant 1201561579 (J.H.); China Postdoctoral Science Foundation grant 2017M622741 (C.Q.); and Guangdong Natural Science Foundation 2017A030313471 (K.H.).
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外文
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中科院(CAS)分区：
出版当年[2019]版：
大类 | 2 区 医学
小类 | 2 区 病理学
最新[2025]版：
大类 | 2 区 医学
小类 | 2 区 病理学
JCR分区：
出版当年[2018]版：
Q1 PATHOLOGY
最新[2023]版：
Q1 PATHOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2018版] 出版当年五年平均 出版前一年[2017版] 出版后一年[2019版]

第一作者：
第一作者机构： [1]Department of Abdominal Surgery,Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Abdominal Surgery,Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China [7]School of Medicine, and the Department of Pharmacy,College of Pharmacy, Jinan University, Guangzhou, China [*1]Department of Abdominal Surgery, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, No.13, Shi Liu Gang Road, Haizhu District, Guangzhou, Guangdong 510315, China
推荐引用方式(GB/T 7714)：
Zheng Dandan,Jiang Yuchuan,Qu Chen,et al.Pyruvate kinase M2 (PKM2) tetramerization protects against hepatic stellate cell activation and liver fibrosis.[J].AMERICAN JOURNAL OF PATHOLOGY.2020,190(11):2267-2281.doi:10.1016/j.ajpath.2020.08.002.
APA：
Zheng Dandan,Jiang Yuchuan,Qu Chen,Yuan Hui,Hu Kaishun...&Hong Jian.(2020).Pyruvate kinase M2 (PKM2) tetramerization protects against hepatic stellate cell activation and liver fibrosis..AMERICAN JOURNAL OF PATHOLOGY,190,(11)
MLA：
Zheng Dandan,et al."Pyruvate kinase M2 (PKM2) tetramerization protects against hepatic stellate cell activation and liver fibrosis.".AMERICAN JOURNAL OF PATHOLOGY 190..11(2020):2267-2281

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