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The cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through RORα and SRC-2 coactivator

Andre Madsen1, Jan-Inge Bjune1, Lise Bjørkhaug2

  • 1Department of Clinical Science K2, University of Bergen, N-5020 Norway; The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway.

Molecular and Cellular Endocrinology
|October 13, 2015
PubMed

Insights

Fasting hormones activate glucose production. Protein kinase A (PKA) inhibits SRC-2 coactivation of RORα, reducing glucose-6-phosphatase (G6Pase) expression and gluconeogenesis during starvation.

Area of Science:

  • Metabolism
  • Molecular Biology
  • Endocrinology

Background:

  • Fasting hormones activate the cAMP/PKA pathway, stimulating hepatic gluconeogenic enzymes like glucose-6-phosphatase (G6Pase).
  • Steroid receptor coactivator 2 (SRC-2) knockout mice show fasting hypoglycemia, and SRC-2 coactivates RAR-related orphan receptor alpha (RORα) at the G6Pase promoter.

Purpose of the Study:

  • Investigate upstream regulation of the RORα/SRC-2 complex on G6Pase expression.
  • Elucidate the functional implications of this complex in gluconeogenesis.

Main Methods:

  • Utilized HepG2 cells for overexpression and knock-down experiments.
  • Employed transactivation assays with G6Pase promoter constructs.
  • Assessed protein levels, promoter recruitment, and coactivation capabilities.

Main Results:

  • Overexpression of the catalytic PKA subunit (PKA-Cα) decreased SRC-2 protein levels and its coactivation of RORα.
  • RORα and SRC-2 are essential for PGC-1α to stimulate G6Pase expression.
  • PKA inhibits SRC-2 coactivation of RORα, reducing PGC-1α-dependent G6Pase regulation.

Conclusions:

  • PKA negatively regulates SRC-2 coactivation of RORα.
  • This indirect feedback mechanism suppresses gluconeogenesis during prolonged starvation.
  • Highlights a novel regulatory pathway for hepatic glucose production.
Keywords:
G6PaseGluconeogenesisPGC-1αRORαSRC-2

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