CRTC2 is a coactivator of GR and couples GR and CREB in the regulation of hepatic gluconeogenesis

Micah J. Hill, Shigeru Suzuki, James H. Segars, Tomoshige Kino

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Glucocorticoid hormones play essential roles in the regulation of gluconeogenesis in the liver, an adaptive response that is required for the maintenance of circulating glucose levels during fasting. Glucocorticoids do this by cooperating with glucagon, which is secreted from pancreatic islets to activate the cAMP-signaling pathway in hepatocytes. The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting. We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. CRTC2 physically interacts with the ligand-binding domain of the GR through a region spanning amino acids 561693. Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB. CRTC2 is required for the maintenance of blood glucose levels during fasting in mice by enhancing the GR transcriptional activity on both the G6p and phosphoenol-pyruvate carboxykinase (Pepck) genes. Finally, CRTC2 modulates the transcriptional activity of the progesterone receptor, indicating that it may influence the transcriptional activity of other steroid/nuclear receptors. Taken together, these results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/ GRand glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.

Original languageEnglish
Pages (from-to)104-117
Number of pages14
JournalMolecular Endocrinology
Volume30
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016

Fingerprint

Cyclic AMP Response Element-Binding Protein
Gluconeogenesis
Glucocorticoid Receptors
Glucocorticoids
Glucagon
Liver
Fasting
Maintenance
Genes
Glucose-6-Phosphatase
Steroid Receptors
Progesterone Receptors
Cytoplasmic and Nuclear Receptors
Pyruvic Acid
Islets of Langerhans
Genetic Promoter Regions
Blood Glucose
Hepatocytes
Hormones
Ligands

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

CRTC2 is a coactivator of GR and couples GR and CREB in the regulation of hepatic gluconeogenesis. / Hill, Micah J.; Suzuki, Shigeru; Segars, James H.; Kino, Tomoshige.

In: Molecular Endocrinology, Vol. 30, No. 1, 01.01.2016, p. 104-117.

Research output: Contribution to journalArticle

Hill, Micah J. ; Suzuki, Shigeru ; Segars, James H. ; Kino, Tomoshige. / CRTC2 is a coactivator of GR and couples GR and CREB in the regulation of hepatic gluconeogenesis. In: Molecular Endocrinology. 2016 ; Vol. 30, No. 1. pp. 104-117.
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