FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states.
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.
Kemper
Jongsook Kim
JK
Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL 61801, USA. jongsook@uiuc.edu
Xiao
Zhen
Z
Ponugoti
Bhaskar
B
Miao
Ji
J
Fang
Sungsoon
S
Kanamaluru
Deepthi
D
Tsang
Stephanie
S
Wu
Shwu-Yuan
SY
Chiang
Cheng-Ming
CM
Veenstra
Timothy D
TD
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
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