title: A crucial role of hepatocyte nuclear factor-4 expression in the differentiation of human ductular hepatocytes.
abstract: Ductular structures are suggested to be bipotential progenitor cells that may differentiate into hepatocytes or biliary epithelial cells (BEC). To better understand the differentiation process, we studied the expression of hepatocyte nuclear factor (HNF) in ductular structures. Matured hepatocytes in normal liver expressed HNF-1, HNF-4alpha, HNF-3beta, and C/EBPalpha in the nucleus. Normal BEC expressed HNF-1 but did not express HNF-4alpha, suggesting an important role of HNF-4alpha in maintaining the phenotype of matured hepatocytes. Ductular structures were classified into ductular cells and ductular hepatocytes. Ductular cells showed glandular or bile duct-like appearance and strongly expressed cytokeratin-7. Ductular hepatocytes showed features between BEC and hepatocytes and heterogeneously expressed cytokeratin-7. Both ductular cells and ductular hepatocytes expressed HNF-4alpha, but the nuclear localization of HNF-4alpha was more prominent in ductular hepatocytes. The expression of HNF-4alpha mRNA in ductular hepatocytes was demonstrated at the single cell level by laser capture microdissection. Regenerative hepatocytes strongly expressed all HNFs in the nucleus, whereas residual hepatocytes in massive necrosis showed low or cytoplasmic expression. These results suggest that HNF-4alpha plays an important role in the differentiation and maintenance of the matured hepatocyte phenotype and that nuclear localization of HNFs is implicated in the accomplishment of their function.
authors.affiliation: Department of Medicine and Medical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hakoda
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Terada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Okano
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Motowo
authors.initials: M
authors.lastname: Mizuno
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shiratori
mesh_terms: D000328:Adult; D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D051557:Hepatocyte Nuclear Factor 4; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D053552:Keratin-7; D007633:Keratins / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C507497:KRT7 protein, human; D053552:Keratin-7; C403128:MLX protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D007633:Keratins