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 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.

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

“…It is widely known that an increase of triglyceride synthesis in liver plays an important role in NAFLD models [14,[21][22][23]. In rodents, an increase in the amount of synthesized lipids was observed in liver and adipose tissue cells, while in humans, it was primarily in the liver.…”

Suppressive effect of ursodeoxycholic acid on type IIA phospholipase A2 expression in HepG2 cells

“…39 Recent investigation indicated that the nuclear farnesoid x receptor and oxysterol x receptor bind bile acids, resulting in a positive/negative regulation in the transcription of several gene products. [40][41][42][43][44] However, there is no binding site for these nuclear receptors in the human PLA 2 IIA gene promoter. 39 In addition, UDCA has been reported to have a limited affinity for these nuclear receptors.…”

Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration

“…Cell culture medium containing retrovirus was collected 48 h after transfection. For cell transduction, 2 ml of viral stock and 8 ml of fresh Dulbecco's modified Eagle's medium were mixed and added in a 100-mm dish of 0.5 ϫ 10 6 BOECs with 8 g/ml Polybrene. Transduction efficiency using this approach was uniformly Ͼ90%.…”