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Submitted on March 29, 2002
Accepted on November 13, 2002
(PPAR) GENE VIA ACTIVATION OF THE FARNESOID X RECEPTOR
1 U.545 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille, 1 Rue Calmette, 59019 Lille, and the Faculté de Pharmacie, Université de Lille II, 59006 Lille, France.Institute of experimental Cardiology, Russian Cardiology Complex, Moscow, Russia.; Current address: Department of Microbiology and the Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Ave., New York, NY 10016.
* To whom correspondence should be addressed. E-mail: Bart.Staels{at}pasteur-lille.fr.
Peroxisome proliferator-activated receptor 
(PPAR) is a nuclear receptor that controls lipid and glucose metabolism and exerts anti-inflammatory activities. PPAR is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPAR and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors the regulation of PPAR expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the non-steroidal FXR agonist GW4064 resulted in a significant induction of PPAR mRNA levels. In addition, hPPAR gene expression was up-regulated by taurocholic acid (TCA) in human primary hepatocytes. Cotransfection of FXR/RXR in the presence of CDCA led to up to a 3-fold induction of human PPAR promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPAR promoter (FXRE) that mediates bile acid regulation of this promoter. FXR bound the FXRE site as demonstrated by gel shift analysis and CDCA specifically increased the activity of a heterologous promoter driven by 4 copies of the FXRE. In contrast, neither the murine PPAR promoter, in which the FXRE is not conserved, nor a mouse FXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPAR expression was not regulated in TCA-fed mice. Finally, induction of hPPAR mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPAR target gene CPT-I by PPAR ligands. In concert, these results demonstrate that bile acids stimulate PPAR expression in a species-specific manner via a FXRE located within the human PPAR promoter. These results provide molecular evidence for a cross-talk between the FXR and PPAR pathways in humans.
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