Antiglucocorticoid activity of hepatocyte nuclear factor-6

Glucocorticoids exert their effects on gene transcription through ubiquitou s receptors that bind to regulatory sequences present in many genes. These glucocorticoid receptors are present in all cell types, Set glucocorticoid action is controlled in a tissue-specific way, One mechanism for this contr ol relies an tissue-specific transcriptional activators that bind in the vi cinity of the glucocorticoid receptor and are required for receptor action. We now describe a gene-specific and tissue-specific inhibitory mechanism t hrough which glucocorticoid action is repressed by a tissue-restricted tran scription factor, hepatocyte nuclear factor-6 (HNF-6). HNF-6 inhibits the g lucocorticoid-induced stimulation of two genes coding for enzymes of liver glucose metabolism, namely 6-phosphofructo-2-kinase and phosphoenolpyruvate carboxykinase. Binding of HNF-6 to DNA is required for inhibition of gluco corticoid receptor activity. In vitro and in vivo experiments suggest that this inhibition is mediated by a direct HNF-6/glucocorticoid receptor inter action involving the amino-terminal domain of HNF-6 and the DNA-binding dom ain of the receptor. Thus, in addition to its known property of stimulating transcription of liver-expressed genes, HNF-6 can antagonize glucocorticoi d-stimulated gene transcription.