Hepatocyte nuclear factor 1 alpha is an accessory factor required for activation of glucose-6-phosphatase gene transcription by glucocorticoids

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeo stasis, causes glycogen storage disease type la (GSD-la), also know as von Gierke disease. Expression of the G6Pase gene is regulated by multiple horm ones, including glucocorticoids, The synthetic glucocorticoid dexamethasone increased G6Pase mRNA abundance and gene transcription in H4-IIE hepatoma cells. Transient transfection assays demonstrated that the G6Pase promoter was active in H4-IIE cells only in the presence of dexamethasone. The minim al G6Pase promoter was contained within nucleotides -234/+3, which has two putative glucocorticoid response elements (GREs) at nucleotides -178/-164 ( site 1) and -154/-140 (site 2). Electromobility shift and transient transfe ction assays showed that only GRE site 1 was required for glucocorticoid-ac tivated transcription from the G6Pase promoter. Deletion analysis demonstra ted that the DNA elements absolutely essential for glucocorticoid-stimulate d transcription from the G6Pase promoter were contained within nucleotides -234/-212, encompassing binding motifs for hepatocyte nuclear factors (HNFs ) 1 (-226/-212) and 4 (-231/-220). Electromobility shift and cotransfection assays showed that HNF1 alpha bound to its cognate site and mediated trans cription activation of the G6Pase gene by glucocorticoids.