Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor α Gene via Activation of the Farnesoid X Receptor

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARα 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 PPARα 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 PPARα 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 PPARα mRNA levels. In addition, hPPARα 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 PPARα promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARα promoter (α-FXR response element (αFXRE)] that mediates bile acid regulation of this promoter. FXR bound the αFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the αFXRE. In contrast, neither the murine PPARα promoter, in which the αFXRE is not conserved, nor a mouse αFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARα expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARα mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARα target gene carnitine palmitoyltransferase I by PPARα ligands. In concert, these results demonstrate that bile acids stimulate PPARα expression in a species-specific manner via a FXRE located within the human PPARα promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARα pathways in humans.