The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis

Glucocorticoids stimulate gluconeogenesis by increasing the rate of transcr iption of genes that encode gluconeogenic enzymes such as phosphoenolpyruva te carboxykinase (PEPCK) and glucose-6-phosphatase. Previous studies have s hown that hepatic nuclear factor 3 (HNF3) is required as an accessory facto r for several glucocorticoid-stimulated genes, including PEPCK. Here, we sh ow that adenovirus-mediated expression of an HNP3 beta protein with a delet ed C-terminal transactivation domain (HNF3 beta Delta C) reduces the glucoc orticoid-induced expression of the PEPCK and glucose-6-phosphatase genes in H4IIE hepatoma cells. Furthermore, expression of this truncated HNF3 prote in results in a proportionate reduction of glucocorticoid-stimulated glucos e production from lactate and pyruvate in these cells. The expression of HN F3 beta Delta N, in which the N-terminal transactivation domain is deleted, does not exhibit any of these effects. These results provide direct eviden ce that members of the HNF3 family are required for proper regulation of he patic gluconeogenesis. Modulation of the function of the HNF3 family of pro teins might be used to reduce the excessive hepatic production of glucose t hat is an important pathophysiologic feature of diabetes mellitus.