title: Glucocorticoid receptor mediates the gluconeogenic activity of the farnesoid X receptor in the fasting condition.
abstract: The glucocorticoid receptor (GR) is a master gene orchestrating the activation of gluconeogenic genes in the liver in response to food withdrawal. Mechanisms of GR regulation by other nuclear receptors, however, are poorly defined. Here, we report that the farnesoid X receptor (FXR), a bile acid sensor, activates gluconeogenic pathways in the liver and regulates GR expression and activity. FXR-null mice are hypoglycemic in the unfed state and exhibit both a reduced hepatic production of glucose in response to the pyruvate challenge and a decreased expression of two rate-limiting enzymes involved in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), along with blunted liver expression of GR. Treating wild-type mice with a semisynthetic FXR ligand (6E-CDCA) increases the liver expression of GR, PEPCK, and G6Pase. This effect was lost in fed animals, as well as in FXR(-/-) mice. The human and mouse GR promoters contain a conserved FXR-responsive element (an ER-8 sequence) whose activation by FXR ligation leads to GR transcription. GR silencing by siRNA in vitro or its pharmacological antagonism in vivo with mifepristone reverses the effect of FXR activation on expression of gluconeogenic genes. These findings demonstrate that an FXR-GR pathway regulates the activation of hepatic gluconeogenesis in the transition from the unfed to the fed state.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, via E. dal Pozzo, 06122 Perugia, Italy. barbara.renga@unipg.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.forename: Franco
authors.initials: F
authors.lastname: Baldelli
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005215:Fasting / Q000378:metabolism*; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D005952:Glucose-6-Phosphatase; D008024:Ligands; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C464660:obeticholic acid