Glucagon-Induced Acetylation of Foxa2 Regulates Hepatic Lipid Metabolism

von Meyenn, Ferdinand and Porstmann, Thomas and Gasser, Emanuel and Selevsek, Nathalie and Schmidt, Alexander and Aebersold, Ruedi and Stoffel, Markus. (2013) Glucagon-Induced Acetylation of Foxa2 Regulates Hepatic Lipid Metabolism. Cell metabolism, Vol. 17, H. 3. pp. 436-447.

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Official URL: http://edoc.unibas.ch/dok/A6094004

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Proteomics (Schmidt)
UniBasel Contributors:Schmidt, Alexander
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:17
Deposited On:26 Apr 2013 06:54

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