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Submitted on August 4, 2003
Accepted on October 21, 2003
-hydroxylase gene (CYP7A1) by thyroid hormone in transgenic mice
1 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. E-mail: luis.agellon{at}ualberta.ca.
Thyroid hormones exert significant changes in the metabolism of bile acids. However in humans, the effect of thyroid hormone on cholesterol 7
-hydroxylase (cyp7a), the rate-controlling enzyme in the classical bile acid biosynthetic pathway, remains poorly understood and has been difficult to study directly in vivo. Previous studies from our laboratory have shown that the activity of the human cholesterol 7-hydroxylase gene promoter is repressed by triiodothyronine (T3) in cultured cells. Accordingly, we hypothesized that T3 would negatively regulate human CYP7A1 gene expression in vivo. We tested this hypothesis by inducing hypo and hyperthyroidism in transgenic mice expressing the human CYP7A1 gene. Hypothyroidism did not affect the abundance of human cyp7a mRNA in transgenic mice. In hyperthyroid male mice, human cyp7a mRNA abundance was decreased. No significant change in cyp7a mRNA abundance was observed in hyperthyroid female mice. Gender differences in the amount of cholesterol and bile acids in gallbladder bile were also observed. The data indicate that thyroid hormone can repress the human CYP7A1 gene in transgenic mice but this effect is dependent upon gender in this in vivo model.
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