title: Significance of oestrogen-related receptor γ on biliary epithelial cells in the pathogenesis of primary biliary cirrhosis.
abstract: OBJECTIVE
  Oestrogen has been speculated to play an important role in the pathogenesis of primary biliary cirrhosis (PBC), which mainly affects middle-aged and old-aged females because biliary epithelial cells (BECs) are known to express oestrogen receptors (ERs). Oestrogen-related receptors (ERRs) are constitutively active without oestrogen and competitively inhibit the ER-dependent effects of oestrogen. We clarified the effects of oestrogen and the significance of ERRs along with their association with the pathogenesis of cholangiopathy in PBC.
  
  
  METHODS
  We investigated the expression of ERs and ERRs and the apoptosis-related cell kinetics in BECs using cultured human BECs and human liver specimens.
  
  
  RESULTS
  Although cultured human BECs and the interlobular bile ducts in the liver expressed ERβ, in cultured BECs, oestrogen treatment did not induce significant cell proliferation but increased the expression of a negative cell proliferation regulator (14-3-3σ protein). The cultured BECs constantly expressed ERRα and ERRγ, and oestrogen downregulated the ERRγ expression. Furthermore, the ERRγ expression was determined in the intrahepatic bile ducts and was stronger in the middle-aged and old-aged females, particularly those with PBC, than in the younger females. The ERRγ ligand activated a transcription factor, SP1, and enhanced the expression of the pro-apoptotic Bcl-2 family molecules and Bcl-2 inhibitor-induced apoptosis in cultured BECs.
  
  
  CONCLUSIONS
  Although oestrogen downregulates the ERRγ expression, the increased ERRγ expression under oestrogen-deficient conditions increases the susceptibility to Bcl-2 family-mediated apoptosis in cultured human BECs of females, particularly those with PBC. Understanding the oestrogen-mediated cell kinetics is important for elucidating the pathogenesis of cholangiopathy in PBC.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Kakuda
authors.initials: K
authors.lastname: Yuko
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Division of Pathology, Kanazawa University Hospital, Kanazawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D004958:Estradiol; D047629:Estrogen Receptor beta; D005095:Exoribonucleases; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D016329:Sp1 Transcription Factor; D000097983:ERRalpha Estrogen-Related Receptor; C490917:ESRRG protein, human; C413442:SFN protein, human
keywords: BILIARY; HORMONE; LIVER DISEASE