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.
journal_name
Cell Metabjournal_title
Cell metabolismauthors
von Meyenn F,Porstmann T,Gasser E,Selevsek N,Schmidt A,Aebersold R,Stoffel Mdoi
10.1016/j.cmet.2013.01.014subject
Has Abstractpub_date
2013-03-05 00:00:00pages
436-47issue
3eissn
1550-4131issn
1932-7420pii
S1550-4131(13)00022-3journal_volume
17pub_type
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