TY - JOUR
T1 - FXR Acetylation Is Normally Dynamically Regulated by p300 and SIRT1 but Constitutively Elevated in Metabolic Disease States
AU - Kemper, Jongsook Kim
AU - Xiao, Zhen
AU - Ponugoti, Bhaskar
AU - Miao, Ji
AU - Fang, Sungsoon
AU - Kanamaluru, Deepthi
AU - Tsang, Stephanie
AU - Wu, Shwu Yuan
AU - Chiang, Cheng Ming
AU - Veenstra, Timothy D.
N1 - Funding Information:
We are grateful to P. Puigserver for Ad-siSIRT1 and Ad-flag-SIRT1, P. Edwards for FXR deletion constructs, M. Leid for GST-SIRT1 constructs, R. Sato for plasmids CMV-3 flag-FXR and G4DBD-FXR, W. Gu and T. Finkel for plasmids for SIRT1 WT and mutant, M. Ananthanarayanan for (FXRE)3-tk-luc, Yoon K. Lee for the Shp-luc reporter plasmid, and T. Imamura for the HA-Ub plasmid. Special thanks to Dr. T.M. Willson for providing GW4064. We also thank B. Kemper for helpful discussions. This study was supported by NIH grants CA103867 and CA124760 to C.-M.C. and NIH DK062777, NIH DK80032, and ADA basic research award to J.K.K. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health under Contract N01-CO-12400 to T.D.V.
PY - 2009/11/4
Y1 - 2009/11/4
N2 - 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 RXRα, 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.
AB - 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 RXRα, 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.
KW - HUMDISEASE
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U2 - 10.1016/j.cmet.2009.09.009
DO - 10.1016/j.cmet.2009.09.009
M3 - Article
C2 - 19883617
AN - SCOPUS:70350606061
SN - 1550-4131
VL - 10
SP - 392
EP - 404
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -