Glucose homeostasis in mammals is maintained, in large parts, through the hypothalamic-pituitary-hormonal
axis (HPA) resulting in the regulation of adrenal glucocorticoid production. Glucocorticoids
are critical mediators of liver-specific glucose metabolism the molecular mechanisms
of which remain largely unclear and, consequently, represented the focus of this study.
We were able to show that adenoviral overexpression of nuclear receptor co-factor
RIP140 in hepatocytes strongly promoted glucose production in these cells. RIP140
knock down was found to inhibit glucocorticoid-stimulated activation of the gluconeogenic
key enzyme gene PEPCK. Indeed, endogenous RIP140 was shown to be recruited to the
glucocorticoid-response unit within the PEPCK promoter and to act as a co-activator
for nuclear receptor HNF4 in vivo. Consistently, RIP140 gene knock down resulted in
reduced PEPCK promoter histone acetylation which correlated with the RIP140-dependent
release of promoter-bound acetyltransferase P300. To this end, RIP140 was found to
physically interact with hepatic P300 in a glucocorticoid-dependent manner and to
be required for P300-dependent activation of PEPCK gene transcription. As aberrant
activity of HPA signaling is causative for diabetic hyperglycemia, our results suggest
that the glucocorticoid-dependent activation of gluconeogenic genes by a regulatory
RIP140/HNF4/P300 complex in liver contributes importantly to the pathogenesis of this
disease.
