Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPAR?.

ABSTRACT: Adaptation to fasting involves both Glucocorticoid Receptor (GR?) and Peroxisome Proliferator-Activated Receptor ? (PPAR?) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPAR?, 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, PPAR? and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GR? 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.

SUBMITTER: Ratman D 

PROVIDER: S-EPMC5159533 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature