Transcription factors are major determinants of cell-specific gene expression in all cell types. Studies in rodent liver have shown that alterations in transcription factor expression determine lineage specification during fetal liver development and signify transdifferentiation of cells of the biliary compartment into 'oval' cells and eventually hepatocytes in adult liver. We examined the cellular localization of hepatocyte-or BEC-associated transcription factors in human fetal and adult liver and in diseases in which transdifferentiation between hepatocytes and biliary cells may play a role. In the normal adult human liver, hepatocyte nuclear factor (HNF)4a and HNF6 appeared exclusively in hepatocytes; HNF1b, HNF3a, and HNF3b were observed only in BEC. During fetal development both BEC and hepatocytes expressed HNF3a, HNF3b, and HNF6. HNF1a was expressed only in fetal hepatocytes. We further examined expression of transcription factors in massive hepatic necrosis and in specific types of chronic liver disease. Hepatocyte-associated transcription factors HNF4a and HNF6 also appeared in BEC in massive hepatic necrosis and chronic hepatitis C virus infection. Similarly, HNF3b that is expressed only in BEC in normal adult liver was also observed in hepatocytes in primary biliary cirrhosis and chronic biliary obstruction. These data mimic previous findings in rodents in which hepatocyte-associated transcription factors appear in biliary cells prior to emergence of oval cells, which function as progenitor cells for hepatocytes when the regenerative capacity of the latter is compromised.

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Hepatocyte nuclear factors or HNF regulate the differentiation of hepatocytes and biliary epithelial cells (BEC) from embryonic hepatoblasts. In massive hepatic necrosis (MHN) and in partial hepatectomy models, progeny of BEC in Canals of Herring transform into hepatocytes. Converse transformation of hepatocytes into BEC has been seen in PH rats treated with biliary toxin DAPM and bile duct ligation. We investigated whether alterations in HNF expression in the adult human diseased liver correlate to ductal plate remodeling during hepatogenesis. Immunohistochemical analysis of HNF‐1α/β, 3α/β,4,6, HepPar1 and CK19 were performed on paraffin embedded human specimens from 5 cases each of 1–3rd trimester fetal, adult normal (NL) and diseased livers (biliary obstruction (BO), Budd‐Chiari syndrome (BCS), MHN, HCV, and PBC). HNF‐4α and ‐6 were expressed exclusively in NL hepatocytes and upregulated in BEC and HepPar1+/CK19+ ductules in MHN, HCV and BCS. HNF‐3β, expressed in NL BEC, was expressed in hepatocytes in PBC, BO and BCS. Our data shows that HNF expression correlates to hepatobiliary transdifferentiation in disease states. It may be that depending upon the type of epithelial injury in the liver, HNF expression varies to either drive the production of hepatocytes or biliary epithelial cells. Careful sequential characterization studies may provide important insights into hepatic repair responses.