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Role of Hepatocyte Nuclear Factor 4 Alpha (HNF4α) in Hepatocyte Regeneration

Hepatocyte nuclear factor 4 alpha (HNF4α) is the master regulator of hepatic differentiation because it regulates over 60% of genes involved in hepatocyte specific function. Recent studies from our laboratory have revealed a novel role of HNF4α in regulation of hepatocyte quiescence. These data indicate that HNF4α can suppress proliferation of mature hepatocytes and is down regulated in hepatocellular carcinoma. However, the role of HNF4α in liver regeneration is not known. We examined HNF4α expression and function in liver regeneration after partial hepatectomy (PH) using three‐month‐old male C57BL/6 mice over a two‐week time course. Whereas no change in HNF4α mRNA were detected in regenerating livers, western blot analysis showed a rapid decline in nuclear HNF4α protein levels within 1 hour after PH, which continued until 6 hours. Nuclear HNF4α protein levels began increasing 12 hours post‐PH but remained significantly lower than normal till 3 days post‐PH and recovered to pre‐PH levels at 5 days after PH. Cytoplasmic HNF4α protein levels mimicked the nuclear expression pattern. Expression of several positive target genes of HNF4a involved in hepatocyte differentiation declined and expression of negative target genes of HNF4α involved in cell proliferation increased consisting with HNF4α protein changes. We further studied the role of HNF4α in liver regeneration after PH using conditional hepatocyte‐specific HNF4α knockout mice (HNF4α‐KO). Deletion of HNF4α resulted in high levels of proliferation at 24 hours and sustained higher levels 7 days post‐PH when compared with wild‐type mice. HNF4α‐KO mice exhibited earlier initiation of regeneration and exhibited defect in termination of regeneration. Finally, we investigated the role of HNF4α in HGF and EGF‐stimulated growth of primary rodent hepatocytes using a chemically defined media. Mitogen treatment stimulated hepatocyte proliferation, which coincides with accelerated loss of HNF4α when compared with untreated hepatocytes. Taken together, these data indicate that loss of HNF4α expression and activity is one of the earliest events in initiation of cell cycle after PH. Similarly, re‐expression of HNF4α and restoration of its activity is essential for termination of liver regeneration. These studies, for the first time, demonstrate that HNF4α reprogramming is a critical step in liver regeneration and could have potential therapeutic benefits.