title: Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism.
abstract: Circulating levels of insulin and glucagon reflect the nutritional state of animals and elicit regulatory responses in the liver that maintain glucose and lipid homeostasis. The transcription factor Foxa2 activates lipid metabolism and ketogenesis during fasting and is inhibited via insulin-PI3K-Akt signaling-mediated phosphorylation at Thr156 and nuclear exclusion. Here we show that, in addition, Foxa2 is acetylated at the conserved residue Lys259 following inhibition of histone deacetylases (HDACs) class I-III and the cofactors p300 and SirT1 are involved in Foxa2 acetylation and deacetylation, respectively. Physiologically, fasting states and glucagon stimulation are sufficient to induce Foxa2 acetylation. Introduction of the acetylation-mimicking (K259Q) or -deficient (K259R) mutations promotes or inhibits Foxa2 activity, respectively, and adenoviral expression of Foxa2-K259Q augments expression of genes involved in fatty acid oxidation and ketogenesis. Our study reveals a molecular mechanism by which glucagon signaling activates a fasting response through acetylation of Foxa2.
authors: Institute of Molecular Health Sciences, ETH Zurich, Schafmattstrasse 22, 8093 Zurich, Switzerland.
authors: Ferdinand
authors: F
authors: von Meyenn
authors: Thomas
authors: T
authors: Porstmann
authors: Emanuel
authors: E
authors: Gasser
authors: Nathalie
authors: N
authors: Selevsek
authors: Alexander
authors: A
authors: Schmidt
authors: Ruedi
authors: R
authors: Aebersold
authors: Markus
authors: M
authors: Stoffel
mesh_terms: D000107:Acetylation; D000256:Adenoviridae; D000818:Animals; D001391:Azo Compounds; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005215:Fasting / Q000378:metabolism / Q000502:physiology*; D005822:Genetic Vectors; D005934:Glucagon / Q000378:metabolism*; D056945:Hep G2 Cells; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016296:Mutagenesis / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D034622:RNA Interference; D056564:Sirtuin 1 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D001391:Azo Compounds; D005934:Glucagon; D051542:Hepatocyte Nuclear Factor 3-beta; D006655:Histone Deacetylases; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C496503:Foxa2 protein, mouse; C470545:Sirt1 protein, mouse; C011049:oil red O