title: Reduction of hepatic fibrosis by overexpression of von Hippel-Lindau protein in experimental models of chronic liver disease.
abstract: Hypoxia-inducible factor (HIF)-1α and HIF-2α play an important role in liver fibrosis. von Hippel-Lindau protein (VHL), a key mediator of HIF-α, regulates fibrosis in an organ- and cell-specific way. In this study, human liver samples were collected from hepatitis C-, alcoholic-, and cholestatic-associated fibrotic and healthy individuals. Two mouse models of liver fibrosis were established: bile duct ligation and carbon tetrachloride injection. We constructed adenovirus vectors to overexpress VHL, normoxia-active HIF-α, and lentiviral vectors to silence HIF-α. The results showed that liver sections from fibrosis patients had a lower level of VHL and higher levels of HIF-1α and HIF-2α compared with healthy sections, a finding which was confirmed in mice. Overexpression of VHL attenuated liver fibrosis, downregulated fibrogenic genes, and inhibited liver inflammation, apoptosis, and angiogenesis. Overexpression of VHL was more successful at inhibiting fibrosis compared with silencing HIF-1α plus HIF-2α. Normoxia-active HIF-1α or HIF-2α prevented the inhibitory effect of VHL on liver fibrosis, indicating that attenuating fibrosis via VHL is HIF-1α- and HIF-2α-dependent to some extent. In addition, overexpression of VHL inhibited mouse hepatic stellate cells activation and proliferation and promoted apoptosis. Taken together, VHL may be considered a new target to inhibit liver fibrosis.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Jizhou
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Tian
authors.affiliation: Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.|Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Baolei
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Song
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Shugeng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D002779:Cholestasis / Q000235:genetics / Q000473:pathology; D058625:End Stage Liver Disease / Q000235:genetics* / Q000473:pathology; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics / Q000473:pathology / Q000821:virology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human