The transcriptional co-regulation of hepatic lipid metabolism by GR and PPARα

The Glucocorticoid Receptor α (GRα) and Peroxisome Proliferator-Activated Receptor α (PPARα) are two Nuclear Receptors (NRs) with important roles in metabolism and inflammation control. The agonists of both GR and PPARα are also frequently used in the clinic for the treatment of inflammatory diseases and dyslipidemia, respectively. In contrast to fibrates, which activate PPARα and are relatively safe and well-tolerated drugs, the use of glucocorticoids (GCs) may lead to a multitude of side effects, including metabolic disturbances. The current work was initiated following a study, which demonstrated potential benefits of combining fibrates with GCs. More specifically, our group has shown that co-activation of PPARα and GR corrects GC-induced insulin resistance and glucose intolerance, which are among the typical side effects of GC-based therapies. Besides the potential utilization of these findings for the improvement of GC-based therapies, a better understanding of the cross talk between GR and PPARα is interesting from a basic science perspective as both factors participate in the metabolic adaptation to fasting. Thus, we embarked on a further characterization of the molecular mechanism behind the GR and PPARα cross talk in a genome wide manner, using primary hepatocyte cells as a model. We demonstrate that both factors share a significant fraction of their genomic binding sites and colocalize in the vicinity of lipid metabolic genes, which are cooperatively activated upon combined stimulation with GR- and PPARα-agonists. A subset of those genes switched from transcriptional antagonism to cooperativity when moving from short to prolonged hepatocyte fasting, a phenomenon found to be strongly dependent on the cellular nutritional status. We moreover found that this regulatory switch coincides with recruitment of phospho-AMPK at the proximal promoters of lipid metabolic genes. As such, active AMPK drives GR/PPARα-agonist-dependent cooperative transcription of genes responding to prolonged fasting. Finally, as the ability of exogenous GCs to induce accumulation of fatty acids in primary hepatocytes was completely abolished upon co-triggering PPARα, our results support that the observed cross-talk can also be recapitulated at the metabolite level