title: Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation.
abstract: Alteration of cell surface proteolysis has been proposed to play a role in liver fibrosis, a grave complication of biliary atresia (BA). In this study we investigated the roles of hepatocyte growth factor activator inhibitor (HAI)-1 and -2 in the progression of BA. The expression levels of HAI-1 and -2 were significantly increased in BA livers compared with those in neonatal hepatitis and correlated with disease progression. In BA livers, HAI-1 and -2 were coexpressed in cells involved in ductular reactions. In other selective cholangiopathies, ductular cells positive for HAI-1 or HAI-2 also increased in number. Inflammatory cytokines, growth factors, and bile acids differentially up-regulated expression of HAI-1 and -2 transcripts in fetal liver cells and this induction could be antagonized by a cyclooxygenase-2 inhibitor. Conditioned media from cell lines stably overexpressing HAI-1 or HAI-2 enhanced the fibrogenic activity of portal fibroblasts and stellate cells, suggesting that both proteins might be involved in liver fibrosis. Because HAI-1 and -2 colocalized in ductular reactions sharing similar features to those observed during normal liver development, we sought to investigate the role of HAI-1 and -2 in cholangiopathies by exploring their functions in fetal liver cells. Knockdown of HAI-1 or HAI-2 promoted bidirectional differentiation of hepatoblast-derived cells. In addition, we showed that the hepatocyte growth factor activator, mitogen-activated protein kinase kinase 1, and phosphatidylinositol 3-kinase signaling pathways were involved in hepatic differentiation enhanced by HAI-2 knockdown.
  
  
  CONCLUSIONS
  HAI-1 and -2 are overexpressed in the liver in cholangiopathies with ductular reactions and are possibly involved in liver fibrosis and hepatic differentiation; they could be investigated as disease markers and potential therapeutic targets.
authors: Department of Medical Research, National Taiwan University Hospital, Taiwan.
authors: Hsiang-Po
authors: HP
authors: Huang
authors: Mei-Hwei
authors: MH
authors: Chang
authors: Yi-Tzu
authors: YT
authors: Chen
authors: Hong-Yuan
authors: HY
authors: Hsu
authors: Cheng-Lun
authors: CL
authors: Chiang
authors: Tai-Shan
authors: TS
authors: Cheng
authors: Yao-Ming
authors: YM
authors: Wu
authors: Mu Zon
authors: MZ
authors: Wu
authors: Yu-Chen
authors: YC
authors: Hsu
authors: Chih-Che
authors: CC
authors: Shen
authors: Chun-Nan
authors: CN
authors: Lee
authors: Ya-Hui
authors: YH
authors: Chuang
authors: Chia-Lun
authors: CL
authors: Hong
authors: Yung-Ming
authors: YM
authors: Jeng
authors: Pin-Hsun
authors: PH
authors: Chen
authors: Huey-Ling
authors: HL
authors: Chen
authors: Ming-Shyue
authors: MS
authors: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002779:Cholestasis / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D055166:Hepatic Stellate Cells / Q000166:cytology; D006505:Hepatitis / Q000151:congenital / Q000473:pathology* / Q000503:physiopathology; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008103:Liver Cirrhosis / Q000151:congenital / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; C109148:SPINT2 protein, human; C504591:Spint1 protein, mouse; C533525:Spint2 protein, mouse