• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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.

Pubmed ID: 19883617

Authors

  • Kemper JK
  • Xiao Z
  • Ponugoti B
  • Miao J
  • Fang S
  • Kanamaluru D
  • Tsang S
  • Wu SY
  • Chiang CM
  • Veenstra TD

Journal

Cell metabolism

Publication Data

November 3, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA103867
  • Agency: NCI NIH HHS, Id: CA124760
  • Agency: NIDDK NIH HHS, Id: DK062777
  • Agency: NIDDK NIH HHS, Id: DK80032
  • Agency: NCI NIH HHS, Id: N01-CO-12400
  • Agency: NIDDK NIH HHS, Id: R01 DK062777
  • Agency: NIDDK NIH HHS, Id: R01 DK062777-06A1
  • Agency: NIDDK NIH HHS, Id: R01 DK080032
  • Agency: NIDDK NIH HHS, Id: R01 DK080032-01A2
  • Agency: NIDDK NIH HHS, Id: R56 DK062777
  • Agency: NIDDK NIH HHS, Id: R56 DK062777-06

Mesh Terms

  • Acetylation
  • Animals
  • Dimerization
  • Disease Models, Animal
  • Down-Regulation
  • Hep G2 Cells
  • Histone Deacetylases
  • Liver
  • Liver Diseases
  • Male
  • Mice
  • Mutagenesis, Site-Directed
  • Protein Stability
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • Retinoid X Receptor alpha
  • Sirtuin 1
  • Stilbenes
  • Transcription Factors
  • Transcriptional Activation
  • p300-CBP Transcription Factors