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Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARU+03B1

Tijdschriftbijdrage - Tijdschriftartikel

Ondertitel:Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPAR alpha
Adaptation to fasting involves both Glucocorticoid Receptor (GRU+03B1) and Peroxisome Proliferator-Activated Receptor U+03B1 (PPARU+03B1) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARU+03B1, 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, PPARU+03B1 and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRU+03B1 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.
Tijdschrift: Nucleic Acids Research
ISSN: 0305-1048
Issue: 22
Volume: 44
Pagina's: 10539 - 10553
Jaar van publicatie:2016