Pharmaceutical Sciences Faculty Publications
Document Type
Article
Publication Date
11-1-2009
Journal Title
Cell Metabolism
ISSN
1932-7420
Volume
10
Issue
5
First Page
392
Last Page
404
DOI
10.1016/j.cmet.2009.09.009
PubMed ID
19883617
PubMed Central® ID
PMC2785075
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.
Keywords
Acetylation, dimerization, liver diseases, protein, RNA
Recommended Citation
Kemper, Jongsook Kim; Xiao, Zhen; Ponugoti, Bhaskar; Miao, Ji; Fang, Sungsoon; Kanamaluru, Deepthi; Tsang, Stephanie; Wu, Shwu-Yuan; Chiang, Cheng-Ming; and Veenstra, Timothy D., "FXR Acetylation is Normally Dynamically Regulated by p300 and SIRT1 but Constitutively Elevated in Metabolic Disease States" (2009). Pharmaceutical Sciences Faculty Publications. 291.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/291