title: FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states.
abstract: The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here, we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRalpha, DNA binding, and transactivation activity. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was dramatically altered, FXR acetylation levels were elevated, and overexpression of SIRT1 or resveratrol treatment reduced acetylated FXR levels. Our data demonstrate that FXR acetylation is normally dynamically regulated by p300 and SIRT1 but is constitutively elevated in metabolic disease states. Small molecules that inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801, USA. jongsook@uiuc.edu
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xiao
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Ponugoti
authors.forename: Ji
authors.initials: J
authors.lastname: Miao
authors.forename: Sungsoon
authors.initials: S
authors.lastname: Fang
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kanamaluru
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tsang
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019281:Dimerization; D004195:Disease Models, Animal; D015536:Down-Regulation; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D055550:Protein Stability / Q000187:drug effects; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated; D000099224:p300-CBP-Associated Factor
chemical_list: D006655:Histone Deacetylases; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000077185:Resveratrol; D047490:Retinoid X Receptor alpha; D056564:Sirtuin 1; D013267:Stilbenes; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; D000099224:p300-CBP-Associated Factor; C470545:Sirt1 protein, mouse