Runt-related transcription factor-1 ameliorates bile acid-induced hepatic inflammation in cholestasis through JAK/STAT3 signaling

作者全名："Zhang, Liangjun; Pan, Qiong; Zhang, Lu; Xia, Haihan; Liao, Junwei; Zhang, Xiaoxun; Zhao, Nan; Xie, Qiaoling; Liao, Min; Tan, Ya; Li, Qiao; Zhu, Jinfei; Li, Ling; Fan, Shijun; Li, Jianwei; Zhang, Chengcheng; Cai, Shi-Ying; Boyer, James L.; Chai, Jin"

作者地址："[Zhang, Liangjun; Pan, Qiong; Zhang, Lu; Xia, Haihan; Liao, Junwei; Zhang, Xiaoxun; Zhao, Nan; Xie, Qiaoling; Liao, Min; Tan, Ya; Li, Qiao; Zhu, Jinfei; Li, Ling; Chai, Jin] Third Mil Med Univ, Affiliated Hosp 1, Inst Digest Dis PLA, Cholestat Liver Dis Ctr,Southwest Hosp,Army Med Un, Chongqing 400038, Peoples R China; [Zhang, Liangjun; Pan, Qiong; Zhang, Lu; Xia, Haihan; Liao, Junwei; Zhang, Xiaoxun; Zhao, Nan; Xie, Qiaoling; Liao, Min; Tan, Ya; Li, Qiao; Zhu, Jinfei; Li, Ling; Chai, Jin] Third Mil Med Univ, Affiliated Hosp 1, Ctr Metab Associated Fatty Liver Dis, Southwest Hosp,Army Med Univ, Chongqing 400038, Peoples R China; [Zhang, Liangjun; Pan, Qiong; Zhang, Lu; Xia, Haihan; Liao, Junwei; Zhang, Xiaoxun; Zhao, Nan; Xie, Qiaoling; Liao, Min; Tan, Ya; Li, Qiao; Zhu, Jinfei; Li, Ling; Chai, Jin] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Digest Dis PLA, Chongqing, Peoples R China; [Zhang, Liangjun; Pan, Qiong; Zhang, Lu; Xia, Haihan; Liao, Junwei; Zhang, Xiaoxun; Zhao, Nan; Xie, Qiaoling; Liao, Min; Tan, Ya; Li, Qiao; Zhu, Jinfei; Li, Ling; Chai, Jin] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Cholestat Liver Dis Ctr, Chongqing, Peoples R China; [Zhang, Liangjun; Pan, Qiong; Zhang, Lu; Xia, Haihan; Liao, Junwei; Zhang, Xiaoxun; Zhao, Nan; Xie, Qiaoling; Liao, Min; Tan, Ya; Li, Qiao; Zhu, Jinfei; Li, Ling; Chai, Jin] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Ctr Metab Associated Fatty Liver Dis, Chongqing, Peoples R China; [Liao, Junwei] Cent South Univ Sch Life Sci, Changsha, Hunan, Peoples R China; [Zhu, Jinfei] Nanchang Univ, Queen Mary Sch, Nanchang, Jiangxi, Peoples R China; [Fan, Shijun] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Med Res Ctr, Chongqing, Peoples R China; [Li, Jianwei; Zhang, Chengcheng] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing, Peoples R China; [Cai, Shi-Ying; Boyer, James L.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT USA; [Cai, Shi-Ying; Boyer, James L.] Yale Univ, Liver Ctr, Sch Med, New Haven, CT USA"

通信作者："Chai, J (通讯作者)，Third Mil Med Univ, Affiliated Hosp 1, Inst Digest Dis PLA, Cholestat Liver Dis Ctr,Southwest Hosp,Army Med Un, Chongqing 400038, Peoples R China.; Chai, J (通讯作者)，Third Mil Med Univ, Affiliated Hosp 1, Ctr Metab Associated Fatty Liver Dis, Southwest Hosp,Army Med Univ, Chongqing 400038, Peoples R China."

来源：HEPATOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000996557500018

JCR分区：Q1

影响因子：12.9

年份：2023

卷号：77

期号：6

开始页：1866

结束页：1881

文献类型：Article

关键词：　

摘要："Background and Aims: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. Approach and Results: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5-ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1-P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2, and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes. Conclusions: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis."

基金机构："National Natural Science Foundation of China [92268110, 81922012]; Outstanding Youth Foundation of Chongqing [cstc2021jcyj-jqX0005]; Project of Chongqing Universities Innovation Research/Outstanding Medical Research Group [2021cqspt01, 4246ZO1]; Science Foundation of Southwest Hospital, China [2017YQRC-01, XZ-2019-505-001, XZ-2019-505-069]; Army Medical University, China [2017YQRC-01, XZ-2019-505-001, XZ-2019-505-069]"

基金资助正文："Supported by grants from the National Natural Science Foundation of China (92268110, 81922012), the Outstanding Youth Foundation of Chongqing (cstc2021jcyj-jqX0005), the Project of Chongqing Universities Innovation Research/Outstanding Medical Research Group (2021cqspt01 and 4246ZO1), and the Science Foundation of Southwest Hospital and Army Medical University (2017YQRC-01, XZ-2019-505-001, and XZ-2019-505-069), China."