title: The cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through RORα and SRC-2 coactivator transcriptional activity.
abstract: Fasting hormones activate the cAMP/PKA signaling pathway and stimulate expression of hepatic gluconeogenic enzymes including glucose-6-phosphatase (G6Pase). Previously it was shown that steroid receptor coactivator 2 (SRC-2) knock-out mice exhibit fasting hypoglycemia and that SRC-2 coactivates RAR-related orphan receptor alpha (RORα) at the proximal G6Pase promoter. We have investigated the upstream regulation and functional implications of this RORα/SRC-2 complex on G6Pase expression. In HepG2 cells, overexpression of the catalytic PKA subunit (PKA-Cα) reduced the SRC-2 protein level, recruitment to the G6Pase promoter, and its ability to coactivate RORα. Knock-down and transactivation experiments employing G6Pase promoter constructs demonstrated that RORα and SRC-2 are required for PGC-1α to stimulate G6Pase expression. These results suggest that PKA inhibits SRC-2 coactivation of RORα and in turn reduces PGC-1α dependent regulation of G6Pase. This indirect feedback mechanism may underlie the suppression of gluconeogenesis throughout long-term starvation.
authors.affiliation: Department of Clinical Science K2, University of Bergen, N-5020 Norway; The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway. Electronic address: Andre.Madsen@k2.uib.no.
authors.forename: Andre
authors.initials: A
authors.lastname: Madsen
authors.affiliation: Department of Clinical Science K2, University of Bergen, N-5020 Norway; The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway. Electronic address: Jan-Inge.Bjune@uib.no.
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Bjune
authors.affiliation: The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway; KG Jebsen Center for Diabetes Research, University of Bergen, N-5020 Norway; Department of Biomedicine, University of Bergen, N-5020 Norway. Electronic address: Lise.Gundersen@k2.uib.no.
authors.forename: Lise
authors.initials: L
authors.lastname: Bjørkhaug
authors.affiliation: Department of Clinical Science K2, University of Bergen, N-5020 Norway; The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway; KG Jebsen Center for Diabetes Research, University of Bergen, N-5020 Norway. Electronic address: Gunnar.Mellgren@med.uib.no.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.affiliation: Department of Clinical Science K2, University of Bergen, N-5020 Norway; The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway; KG Jebsen Center for Diabetes Research, University of Bergen, N-5020 Norway. Electronic address: Jorn.Sagen@k2.uib.no.
authors.forename: Jørn V
authors.initials: JV
authors.lastname: Sagen
mesh_terms: D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D005952:Glucose-6-Phosphatase
keywords: G6Pase; Gluconeogenesis; PGC-1α; RORα; SRC-2