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A Distinct Thyroid Hormone Response Element Mediates Repression of the Human Cholesterol 7-Hydroxylase (CYP7A1) Gene Promoter

Canadian Institutes of Health Research Group in Molecular and Cell Biology of Lipids and Department of Biochemistry (V.A.B.D., L.B.A.), University of Alberta, Edmonton, Alberta, T6G 2S2 Canada; and the Departments of Medicine and Biochemistry and Molecular Biology (N.C.W.W.), University of Calgary, Calgary, Alberta, T2N 4N1 Canada

Address all correspondence and requests for reprints to: Dr. Luis B. Agellon, Department of Biochemistry, 327 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2 Canada. E-mail: luis.agellon{at}ualberta.ca

We examined the molecular basis by which T₃ regulates the human cholesterol 7-hydroxylase gene (CYP7A1) promoter. L-T₃ decreased chloramphenicol acetyltransferase activity in hepatoma cells cotransfected with a plasmid encoding the T₃ receptor (TR) [NR1a1] and a chimeric gene containing nucleotides -372 to +61 of the human CYP7A1 gene fused to the chloramphenicol acetyltransferase structural gene. Deoxyribonuclease I footprinting revealed that recombinant TR protected two regions in this segment of the human CYP7A1 gene promoter. In EMSAs, TR bound to both regions. The binding was competed by oligonucleotides bearing an idealized TR binding motif and abolished by mutation of these elements. In assays of promoter function, mutation of only one of the TR binding sites blocked repression by T₃. The results indicate that T₃-dependent repression of human CYP7A1 gene expression is mediated via a novel site in the human CYP7A1 gene promoter.

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