Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARalpha 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 PPARalpha 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 PPARalpha 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 nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels. In addition, hPPARalpha gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARalpha promoter (alpha-FXR response element (alphaFXRE)] that mediates bile acid regulation of this promoter. FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE. In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARalpha expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARalpha mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARalpha target gene carnitine palmitoyltransferase I by PPARalpha ligands. In concert, these results demonstrate that bile acids stimulate PPARalpha expression in a species-specific manner via a FXRE located within the human PPARalpha promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans.
Pineda Torra
Inés
I
U.545 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.
Claudel
Thierry
T
Duval
Caroline
C
Kosykh
Vladimir
V
Fruchart
Jean-Charles
JC
Staels
Bart
B
D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D047488:Retinoid X Receptors; D013045:Species Specificity; D013656:Taurocholic Acid / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013656:Taurocholic Acid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064