The nuclear receptors ERRa and PPARa co-ordinately control starvation-induced gene expression in hepatocytes.

Peroxisome-proliferator activated receptor a (PPARa) activation reprograms liver gene expression to support fatty acid oxidation during fasting. How PPARa engages in transcriptional programs coping with catabolic fasting responses is insufficiently understood. By applying a protein-protein interaction methodology that also captures transient interactions, we revealed the orphan nuclear receptor estrogen-related receptor a (ERRa) as a novel interaction partner of liganded PPARa and found that this interaction is enhanced following cellular nutrient starvation. Among target genes affected by PPARa-ERRa transcriptional crosstalk in fasted murine livers, multiple components of the electron transport chain were identified. Using pharmacological tools to study hepatic gene subsets under dual PPARa and ERRa control and moving from short-term to prolonged nutrient deprivation, we found that ERRa can switch from being a PPARa target gene suppressor to a marked PPARa target gene activator. Mechanistically, ERRa may control PPARa transcriptional activity via binding onto PPARa's coactivator interaction site and via facilitating cofactor relays. In sum, a variety of crosstalk mechanisms between PPARa and ERRa seems to co-ordinately drive essential gene regulatory changes in the starving hepatocyte. Overall design: The transcriptomic signature underlying the ERRa and PPARa crosstalk in murine hepatocytes using RNA-sequencing of the following conditions: DMSO, PPARa-specific agonist GW7647 (GW), ERRa inverse agonist Compound 29 (C29), GW+C29.