title: Fatty acid binding protein-4 (FABP4) is a hypoxia inducible gene that sensitizes mice to liver ischemia/reperfusion injury.
abstract: OBJECTIVE
  Fatty acid binding protein 4 (FABP4) has been known as a mediator of inflammatory response in the macrophages and adipose tissue, but its hepatic function is poorly understood. The goal of this study is to investigate the role of FABP4 in liver ischemia/reperfusion (I/R), a clinical condition that involves both hypoxia and inflammation.
  
  
  METHODS
  To examine the I/R regulation of FABP4, mice were subjected to I/R surgery before being measured for FABP4 gene expression. Both loss-of-function (by using a pharmacological FABP4 inhibitor) and gain-of-function (by adenoviral overexpression of FABP4) were used to determine the functional relevance of FABP4 expression and its regulation during I/R. To determine the hypoxia responsive regulation of FABP4, primary mouse hepatocytes were exposed to hypoxia. The FABP4 gene promoter was cloned and its regulation by hypoxia inducible factor 1α (HIF-1α) was characterized by luciferase reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays.
  
  
  RESULTS
  We found that the hepatic expression of FABP4 was markedly induced by I/R. At the functional level, pharmacological inhibition of FABP4 alleviated the I/R injury, whereas adenoviral overexpression of FABP4 sensitized mice to I/R injury. We also showed that exposure of primary hepatocytes to hypoxia or transgenic overexpression of HIF-1α in the mouse liver was sufficient to induce the expression of FABP4. Our promoter analysis established FABP4 as a novel transcriptional target of HIF-1α.
  
  
  CONCLUSIONS
  FABP4 is a hypoxia inducible gene that sensitizes mice to liver I/R injury. FABP4 may represent a novel therapeutic target, and FABP4 inhibitors may be used as therapeutic agents to manage hepatic I/R injury.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Bingfang
authors.initials: B
authors.lastname: Hu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Wojciech G
authors.initials: WG
authors.lastname: Garbacz
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Molecular & Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular & Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. Electronic address: huangmin@mail.sysu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wex6@pitt.edu.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D007511:Ischemia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics* / Q000378:metabolism
chemical_list: C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004247:DNA
keywords: FABP4; HIF-1α; Hypoxia; Ischemia/reperfusion; Liver injury