| First Author | Sasaki S | Year | 2018 |
| Journal | Mol Cell Biol | PubMed ID | 30224520 |
| Mgi Jnum | J:267995 | Mgi Id | MGI:6268618 |
| Doi | 10.1128/MCB.00213-18 | Citation | Sasaki S, et al. (2018) Induction of hepatic metabolic functions by a novel variant of hepatocyte nuclear factor 4gamma. Mol Cell Biol |
| abstractText | Hepatocyte nuclear factor 4alpha (HNF4alpha) is a critical factor for hepatocyte differentiation. HNF4alpha expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4gamma was increased in liver-specific Hnf4a-null mice. The increased HNF4gamma contained two variants, a known short variant, designated HNF4gamma1, and a novel long variant, designated HNF4gamma2. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF4gamma2 was the strongest among these variants, but the potential of HNF4gamma1 was the lowest. Co-transfection experiments revealed that HNF4gamma1 repressed HNF4alpha- and HNF4gamma2-dependent transactivation while HNF4gamma2 promoted the HNF4alpha-dependent transactivation. HNF4gamma1 and HNF4gamma2 were able to bind to the HNF4alpha binding sites with similar affinity as HNF4alpha. Furthermore, HNF4gamma2, but not HNF4gamma1, robustly induced expression of typical HNF4alpha target genes to a greater degree than did HNF4alpha. Additionally, HNF4gamma2 suppressed proliferation of hepatoma cells as well as HNF4alpha and HNF4gamma1, and HNF4gamma2 induced critical hepatic functions such as glucose and urea production, and CYP1A2 activity stronger than did HNF4alpha and HNF4gamma1. These results indicate that HNF4gamma2 has potential for redifferentiation of HCC and thus may be explored as a target for HCC therapy. |
