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Phosphorylation of Farnesoid X Receptor by Protein Kinase C Promotes Its Transcriptional Activity

GENFIT (R.G., A.S., S.H., A.A., R.D., D.W.H.), 59120 Loos-Lez-Lille, France; Institut Pasteur de Lille (R.P., J.-C.F., B.S.); Département d’Athérosclérose; Institut National de la Santé et de la Recherche Médicale Unité 545 (R.G., R.P., J.-C.F, B.S.); Lille F-59019, France; and Université de Lille 2 (R.P., J.-C.F., B.S.), Faculté de Pharmacie, Faculté de Médecine, Lille F-59006, France

Address all correspondence and requests for reprints to Bart Staels: Unité de Recherche 545 Institut National de la Santé et de la Recherche Médicale, 1 rue du Prof Calmette, Boîte Postale 245 59019 Lille, Cedex, France. E-mail: Bart.Staels{at}pasteur-lille.fr.

The farnesoid X receptor (FXR, NR1H4) belongs to the nuclear receptor superfamily and is activated by bile acids such as chenodeoxycholic acid, or synthetic ligands such as GW4064. FXR is implicated in the regulation of bile acid, lipid, and carbohydrate metabolism. Posttranslational modifications regulating its activity have not been investigated yet. Here, we demonstrate that calcium-dependent protein kinase C (PKC) inhibition impairs ligand-mediated regulation of FXR target genes. Moreover, in a transactivation assay, we show that FXR transcriptional activity is modulated by PKC. Furthermore, phorbol 12-myristate 13-acetate , a PKC activator, induces the phosphorylation of endogenous FXR in HepG2 cells and PKC phosphorylates in vitro FXR in its DNA-binding domain on S135 and S154. Mutation of S135 and S154 to alanine residues reduces in cell FXR phosphorylation. In contrast to wild-type FXR, mutant FXRS135AS154A displays an impaired PKC-induced transactivation and a decreased ligand-dependent FXR transactivation. Finally, phosphorylation of FXR by PKC promotes the recruitment of peroxisomal proliferator-activated receptor coactivator 1. In conclusion, these findings show that the phosphorylation of FXR induced by PKC directly modulates the ability of agonists to activate FXR.

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  FXRα

Coregulators:   PGC-1

Ligands:   GW4064