Control of hepatic gluconeogenesis through nuclear receptor co-factor RIP140

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.