Editors' ChoiceMetabolism

Dynamic Deacetylation

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Science Signaling  10 Nov 2009:
Vol. 2, Issue 96, pp. ec365
DOI: 10.1126/scisignal.296ec365

Kemper et al. report that the farnesoid X receptor (FXR)—a nuclear receptor activated by bile acids that contributes to control of glucose and lipid metabolism—is regulated in a complex manner by acetylation. In mammalian liver cells, acetylation of FXR on the one hand increased stability of the protein (apparently by inhibiting proteasome-dependent degradation) and on the other decreased its transcriptional activity. Mutation of the acetylated lysine residues promoted association of FXR with RXR (retinoid X receptor), with which FXR forms active dimers that activate transcription. FXR is acetylated by the p300 protein, and Kemper et al. showed that FXR also associated with the deacetylase SIRT1 and is a substrate for that enzyme. SIRT is the focus of great attention because it has important effects on metabolism and longevity and because activation of SIRT1 has a beneficial effect in animals with metabolic disease. Chromatin immunoprecipitation studies showed that activation of FXR by ligand binding caused dissociation of SIRT1 from promoter complexes. Depletion of SIRT1 with siRNA increased acetylation of FXR and interfered with proper lipid metabolism. In mouse models of obesity and type II diabetes, acetylation of FXR was increased. Treatments that enhanced activity of SIRT1 and improved metabolic function also reduced this excessive acetylation of FXR. The authors offer a model of regulation of FXR target genes in which activation of FXR promotes dissociation from SIRT1 and association with p300. Consequent acetylation of histones contributes to gene activation, whereas acetylation of FXR inhibits its activity, presumably as a negative feedback reaction that contributes to dynamic regulation of gene transcription. Given the correlation of excessive acetylation of FXR with metabolic abnormalities associated with metabolic disease, the authors suggest that inhibition of acetylation of FXR through regulation of p300 or SIRT1 might be therapeutically useful.

J. K. Kemper, Z. Xiao, B. Ponugoti, J. Miao, S. Fang, D. Kanamaluru, S. Tsang, S.-Y. Wu, C.-M. Chiang, T. D. Veenstra, FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 10, 392–404 (2009). [PubMed]

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