Beta‐catenin/TCF complex regulates HNF4‐alpha expression in the liver

Abstract

Hepatocyte nuclear factor‐alpha (HNF4α) is a liver‐enriched nuclear receptor of the steroid and thyroid hormone receptor superfamily. It is expressed at the highest levels in the liver, kidney, intestine, and pancreas, and plays an essential role in development, organogenesis, and maintenance of organ function. Previously, we have shown that loss of β‐catenin during prenatal liver development compromises hepatocyte maturation. We identified low HNF4α expression in the β‐catenin‐deficient hepatocytes. Also, livers from transgenic mice overexpressing stable β‐catenin and hepatocyte‐specific β‐catenin knockout mice show high and low HNFα expression, respectively. Here, we investigate the regulation of HNF4α expression by β‐catenin. Transfection of HepG2 cells, a human hepatoma cell line, which harbors constitutively active β‐catenin, with HNF4α‐ reporter plasmids demonstrates high luciferase activity, which was significantly reduced in response to β‐catenin siRNA transfection. Co‐transfection of Hep3B cells (contain wild‐type β‐catenin) with stable β‐catenin plasmid and HNF4α‐promoter luciferase expression plasmid also exhibited high reporter activity. ChIP assays utilizing β‐catenin and TCF antibodies clearly show binding to HNF4α promoter. These data indicate that β‐catenin can directly regulate HNF4α, a nuclear transcription receptor and plays a critical role hepatocyte homeostasis.