Induction Of Hepatic Metabolic Functions By A Novel Variant Of Hepatocyte Nuclear Factor 4 Gamma

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a critical factor for hepatocyte differentiation. HNF4 alpha expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4 gamma was increased in liver-specific Hnf4a-null mice. The HNF4 gamma whose expression was increased contained two variants, a known short variant, designated HNF4 gamma 1, and a novel long variant, designated HNF4 gamma 2. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF4 gamma 2 was the strongest among these variants, but the potential of HNF4 gamma 1 was the lowest. Cotransfection experiments revealed that HNF4 gamma 1 repressed HNF4 alpha- and HNF4 gamma 2-dependent transactivation, while HNF4 gamma 2 promoted HNF4 alpha-dependent transactivation. HNF4 gamma 1 and HNF4 gamma 2 were able to bind to the HNF4 alpha binding sites with an affinity similar to that of HNF4 alpha. Furthermore, HNF4 gamma 2, but not HNF4 gamma 1, robustly induced the expression of typical HNF4 alpha target genes to a greater degree than HNF4 alpha. Additionally, HNF4 gamma 2 suppressed proliferation of hepatoma cells as well as HNF4 alpha and HNF4 gamma 1 did, and HNF4 gamma 2 induced critical hepatic functions, such as glucose and urea production, and cytochrome P450 1A2 activity more strongly than HNF4 alpha and HNF4 gamma 1 did. These results indicate that HNF4 gamma 2 has potential for redifferentiation of HCC and thus may be explored as a target for HCC therapy.