Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα
(2016) Nucleic Acids Research — Vol. 44, n° 22, p. 10539-10553 (2016)
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Rider, Mark H. 
- Abstract
- Adaptation to fasting involves both Glucocorticoid Receptor (GRα) and Peroxisome Proliferator-Activated Receptor α (PPARα) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARα, using ChIP- and RNA-seq in primary hepatocytes. Our data reveal extensive chromatin co-localization of both factors with cooperative induction of genes controlling lipid/glucose metabolism. Key GR/PPAR co-controlled genes switched from transcriptional antagonism to cooperativity when moving from short to prolonged hepatocyte fasting, a phenomenon coinciding with gene promoter recruitment of phosphorylated AMP-activated protein kinase (AMPK) and blocked by its pharmacological inhibition. In vitro interaction studies support trimeric complex formation between GR, PPARα and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRα Ser211. Phospho-AMPK chromatin recruitment at liver target genes, observed upon prolonged fasting in mice, is dampened by refeeding. Taken together, our results identify phospho-AMPK as a molecular switch able to cooperate with nuclear receptors at the chromatin level and reveal a novel adaptation mechanism to prolonged fasting.
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Ratman, D., Mylka, V., Bougarne, N., Pawlak, M., Caron, S., Hennuyer, N., Paumelle, R., De Cauwer, L., Thommis, J., Rider, M. H., Libert, C., Lievens, S., Tavernier, J., Staels, B., & De Bosscher, K. (2016). Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα. Nucleic Acids Research, 44(22), 10539-10553. https://doi.org/10.1093/nar/gkw742 (Original work published 2016)