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

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

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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,treat-ment 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 com-pound 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.Pharmacolog-ical inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.

Alcoholic steatohepatitisFatty acid binding protein 4Pregnane X receptor,Alcoholic liver diseaseAndrographolideNuclear receptor,Liver injuryRifampicin

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

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Institute of Clinical Pharmacology,School of Pharmaceutical Sciences,Sun Yat-sen University Guangzhou 510006,China

Department of Electrical Engineering and Computer Science,Case School of Engineering,Case Western Reserve University,Cleveland,OH 44106,USA

Research Center for Drug Metabolism,School of Life Sciences,Jilin University,Changchun 130015,China

Department of Hepatobiliary and Pancreatic Surgery,Zhongnan Hospital of Wuhan University,School of Pharmaceutical Sciences,Wuhan University,Wuhan 430072,China

Department of Pharmacology,Shantou University Medical College,Shantou 515031,China

Department of Endocrinology and Metabolic Disease,the First Affiliated Hospital,Zhejiang UniversitySchool of Medicine,Hangzhou 310003,China

Re search Center for Drug Discovery,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

Department of Orthodontics,School of Stomatology,Capital Medical University Beijing 100069,China

School of Food and Drug,Shenzhen Polytechnic University,Shenzhen 518055,China

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2024

10.1016/j.apsb.2024.08.029

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(11)