The inhibition of the human cholesterol 7alpha-hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor alpha and peroxisome proliferator-activated receptor alpha heterodimer |
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Authors: | Gbaguidi G Franck Agellon Luis B |
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Institution: | 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. |
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Abstract: | In previous work, we showed that the binding of the liver x receptor α:peroxisome proliferator-activated receptor α (LXRα:PPARα) heterodimer to the murine Cyp7a1 gene promoter antagonizes the stimulatory effect of their respective ligands. In this study, we determined if LXRα:PPARα can also regulate human CYP7A1 gene promoter activity. Co-expression of LXRα and PPARα 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 LXRα:PPARα, although with substantially less affinity compared with the murine Cyp7a1 Site I. The binding of LXRα:PPARα to human CYP7A1 Site I was increased in the presence of either LXRα or PPARα 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 LXRα and PPARα. However, a derivative of the human CYP7A1 gene promoter that contains a mutant form of Site I that does not bind LXRα:PPARα was not inhibited by WY 14,643 or 25-hydroxycholesterol in both McArdle RH7777 and HepG2 cells. The ligand-dependent recruitment of LXRα:PPARα 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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