Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4 was increased in liver-specific Hnf4a-null mice. The HNF4 whose expression was increased contained two variants, a known short variant, designated HNF41, and a novel long variant, designated HNF42. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF42 was the strongest among these variants, but the potential of HNF41 was the lowest. Cotransfection experiments revealed that HNF41 repressed HNF4α- and HNF42-dependent transactivation, while HNF42 promoted HNF4α-dependent transactivation. HNF41 and HNF42 were able to bind to the HNF4α binding sites with an affinity similar to that of HNF4α. Furthermore, HNF42, but not HNF41, robustly induced the expression of typical HNF4α target genes to a greater degree than HNF4α. Additionally, HNF42 suppressed proliferation of hepatoma cells as well as HNF4α and HNF41 did, and HNF42 induced critical hepatic functions, such as glucose and urea production, and cytochrome P450 1A2 activity more strongly than HNF4α and HNF41 did. These results indicate that HNF42 has potential for redifferentiation of HCC and thus may be explored as a target for HCC therapy.

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