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Published online 11 February 2004

Nucleic Acids Research, 2004, Vol. 32, No. 3 1113-1121
© 2004 Oxford University Press

The inhibition of the human cholesterol 7{alpha}-hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor {alpha} and peroxisome proliferator-activated receptor {alpha} heterodimer

G. Franck Gbaguidi and Luis B. Agellon

Canadian Institutes of Health Research Group in Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

*To whom correspondence should be addressed. Tel: +1 780 492 5251; Fax: +1 780 492 3383; Email: luis.agellon{at}ualberta.ca
Present address: G. Franck Gbaguidi, INSERM U462, Hôpital Saint-Louis, Institut d’Hématologie, Paris, France

In previous work, we showed that the binding of the liver x receptor {alpha}:peroxisome proliferator-activated receptor {alpha} (LXR{alpha}:PPAR{alpha}) heterodimer to the murine Cyp7a1 gene promoter antagonizes the stimulatory effect of their respective ligands. In this study, we determined if LXR{alpha}:PPAR{alpha} can also regulate human CYP7A1 gene promoter activity. Co-expression of LXR{alpha} and PPAR{alpha} in McArdle RH7777 hepatoma cells decreased the activity of the human CYP7A1 gene promoter in response to fibrates and 25-hydroxycholesterol. In vitro, the human CYP7A1 Site I bound LXR{alpha}:PPAR{alpha}, although with substantially less affinity compared with the murine Cyp7a1 Site I. The binding of LXR{alpha}:PPAR{alpha} to human CYP7A1 Site I was increased in the presence of either LXR{alpha} or PPAR{alpha} ligands. In HepG2 hepatoblastoma cells, fibrates and 25-hydroxycholesterol inhibited the expression of the endogenous CYP7A1 gene as well as the human CYP7A1 gene promoter when co-transfected with plasmids encoding LXR{alpha} and PPAR{alpha}. However, a derivative of the human CYP7A1 gene promoter that contains a mutant form of Site I that does not bind LXR{alpha}:PPAR{alpha} was not inhibited by WY 14,643 or 25-hydroxycholesterol in both McArdle RH7777 and HepG2 cells. The ligand-dependent recruitment of LXR{alpha}:PPAR{alpha} heterodimer onto the human CYP7A1 Site I can explain the inhibition of the human CYP7A1 gene promoter in response to fibrates and 25-hydroxycholesterol.


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