The cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through ROR alpha and SRC-2 coactivator transcriptional activity

摘要

Fasting hormones activate the cAMP/PICA 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 (ROR alpha) at the proximal G6Pase promoter. We have investigated the upstream regulation and functional implications of this RORa/SRC-2 complex on G6Pase expression. In HepG2 cells, overexpression of the catalytic PICA subunit (PICA-C alpha) reduced the SRC-2 protein level, recruitment to the G6Pase promoter, and its ability to coactivate ROR alpha. Knock-down and transactivation experiments employing G6Pase promoter constructs demonstrated that RORa and SRC-2 are required for PGC-1 alpha to stimulate G6Pase expression. These results suggest that PICA inhibits SRC-2 coactivation of RORa and in turn reduces PGC-1 alpha dependent regulation of G6Pase. This indirect feedback mechanism may underlie the suppression of gluconeogenesis throughout long-term starvation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.