Activation of pregnane X receptor sensitizes alcoholic steatohepatitis by transactivating fatty acid binding protein 4  

作　　者：Yiwen Zhang Bingfang Hu Shaoxing Guan Pan Li Yingjie Guo Pengfei Xu Yongdong Niu Yujin Li Ye Feng Jiewen Du Jun Xu Xiuchen Guan Jingkai Gu Haiyan Sun Min Huang 

机构地区：[1]Institute of Clinical Pharmacology,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]Research Center for Drug Metabolism,School of Life Sciences,Jilin University,Changchun 130015,China [3]Department of Hepatobiliary and Pancreatic Surgery,Zhongnan Hospital of Wuhan University,School of Pharmaceutical Sciences,Wuhan University,Wuhan 430072,China [4]Department of Pharmacology,Shantou University Medical College,Shantou 515031,China [5]Department of Endocrinology and Metabolic Disease,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [6]Research Center for Drug Discovery,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [7]Department of Orthodontics,School of Stomatology,Capital Medical University,Beijing 100069,China [8]Department of Electrical Engineering and Computer Science,Case School of Engineering,Case Western Reserve University,Cleveland,OH 44106,USA [9]School of Food and Drug,Shenzhen Polytechnic University,Shenzhen 518055,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第11期4776-4788,共13页药学学报（英文版）

基　　金：National Natural Science Foundation of China(Grant Nos.82020108031,82404752,81730103,81573507 and 81973398);National Key Research and Development Program(Grant Nos.2017YFC0909300 and 2016YFC0905000,China);Guangdong Provincial Key Laboratory of Construction Foundation(Grant Nos.2017B030314030 and 2020B1212060034,China);Science and Technology Program of Guangzhou(Grant No.201607020031,China);National Engineering and Technology Research Center for New drug Druggability Evaluation Seed Program of Guangdong Province(Grant No.2017B090903004,China);111 project(Grant No.B16047,China);Guangdong Basic and Applied Basic Research Foundation(Grant Nos.2022A1515012549 and 2023A1515012667,China);Marine Medicine Innovation Platform for the Integration of Production and Education Project of Guangdong Provincial Education Department(No.2021CJPT014,China);Shenzhen Stability Support Project for Colleges and Universities(No.20220814205518001,China);Shenzhen Sustainable Development Project(No.KCXFZ20230731094501002,China).

摘　　要：Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the liver tissue as a result of excessive alcohol consumption. Pregnane X receptor (PXR) is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition. Clinical reports suggested that the antibiotic rifampicin, a potent human PXR activator, is a contraindication in alcoholics, but the mechanism was unclear. In this study, we showed that the hepatic expression of fatty acid binding protein 4 (FABP4) was uniquely elevated in ASH patients and a mouse model of ASH. Pharmacological inhibiting FABP4 attenuated ASH in mice. Furthermore, treatment of mice with the mouse PXR agonist pregnenolon-16α-carbonitrile (PCN) induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner. Our mechanism study established FABP4 as a transcriptional target of PXR. Treatment with andrographolide, a natural compound and dual inhibitor of PXR and FABP4, alleviated mice from ASH. In summary, our results showed that the PXR-FABP4 gene regulatory axis plays an important role in the progression of ASH, which may have accounted for the contraindication of rifampicin in patients of alcoholic liver disease. Pharmacological inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.

关 键 词：Alcoholic steatohepatitis Fatty acid binding protein 4 Pregnane X receptor Alcoholic liver disease ANDROGRAPHOLIDE Nuclear receptorLiver injury RIFAMPICIN 

分 类 号：R575[医药卫生—消化系统]