The cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through RORα and SRC-2 coactivator transcriptional activity. (5th January 2016)

• Record Type: Journal Article
• Authors: Madsen, Andre; Bjune, Jan-Inge; Bjørkhaug, Lise; Mellgren, Gunnar; Sagen, Jørn V.
• Is Part Of: Molecular and cellular endocrinology. Volume 419(2016)
• Page Start: 92
• Page End: 101
• Publication Date: 2016-01-05
• Subjects: Gluconeogenesis -- SRC-2 -- RORα -- G6Pase -- PGC-1α; G6Pase glucose-6-phosphatase -- SRC steroid receptor coactivator -- PKA protein kinase A/cAMP-dependent protein kinase -- RORα retinoic acid related orphan receptor alpha -- RORE RORα response element -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- HNF4α hepatocyte nuclear factor 4-alpha; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.10.003
• Languages: English
• ISSNs: 0303-7207

Abstract

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. Highlights: RORα and its coactivator SRC-2 promote expression of hepatic G6Pase. RORα/SRC-2 facilitate PGC-1α dependent activation of the G6Pase promoter. Potent PKA activity causes degradation of SRC-2. PKA reduces recruitment of SRC-2 and RNA Polymerase II to the G6Pase promoter. This mechanism may suppress gluconeogenesis during long-term starvation.