| First Author | Ratman D | Year | 2016 |
| Journal | Nucleic Acids Res | Volume | 44 |
| Issue | 22 | Pages | 10539-10553 |
| PubMed ID | 27576532 | Mgi Jnum | J:247211 |
| Mgi Id | MGI:5923947 | Doi | 10.1093/nar/gkw742 |
| Citation | Ratman D, et al. (2016) Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARalpha. Nucleic Acids Res 44(22):10539-10553 |
| abstractText | Adaptation to fasting involves both Glucocorticoid Receptor (GRalpha) and Peroxisome Proliferator-Activated Receptor alpha (PPARalpha) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARalpha, 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, PPARalpha and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRalpha 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. |
