title: Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice.
abstract: Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Takayo
authors.initials: T
authors.lastname: Takemura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiso
authors.forename: Takashi
authors.initials: T
authors.lastname: Kizu
authors.forename: Kunimaro
authors.initials: K
authors.lastname: Furuta
authors.forename: Hisao
authors.initials: H
authors.lastname: Ezaki
authors.forename: Mina
authors.initials: M
authors.lastname: Hamano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Egawa
authors.forename: Norihiro
authors.initials: N
authors.lastname: Chatani
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Imai
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.forename: Eisuke
authors.initials: E
authors.lastname: Mekada
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins
keywords: ALP; ALT; BDL; Bile duct ligation; EGF; H&E; HB-EGF; HSCs; Heparin-binding EGF-like growth factor; Hepatic stellate cells; KO; Liver fibrosis; RT-PCR; T.Bil; TGF-β; TNF-α; Transforming growth factor-β; WT; alanine aminotransferase; alkaline phosphatase; bile duct ligation; epidermal growth factor; hematoxylin and eosin; heparin-binding EGF-like growth factor; hepatic stellate cells; knockout; poly I:C; polyinosinic:polycytidylic acid; reverse-transcription polymerase chain reaction; total bilirubin; transforming growth factor-β; tumor necrosis factor-α; wild type