HORMONAL-REGULATION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE SPECIFIC ACTIVITY, MESSENGER-RNA LEVELS, AND TRANSCRIPTIONAL ACTIVITY IN-VIVO IN THERAT

In primary cultures of rat hepatocytes, transcription of the cholester ol 7 alpha-hydroxylase gene is induced synergistically by glucocortico id and thyroid hormones. The objective of the present study was to eva luate the role of glucocorticoid and thyroid hormones in the maintenan ce of cholesterol 7 alpha-hydroxylase gene expression in vivo. Male Sp rague-Dawley rats underwent adrenalectomy (A), thyroidectomy (T), adre nalectomy + thyroidectomy (A + T), hypophysectomy (H), or sham surgery (paired controls). Ten days post surgery, livers were harvested and c holesterol 7 alpha-hydroxylase specific activity, steady-state mRNA le vels, and transcriptional activity were determined. Serum corticostero ne levels were <2% of paired controls in A, A + T and H rats. Free thy roxine index was <32% of paired controls in rats with T and H. When co mpared to sham-operated controls, A + T and H led to decreases in chol esterol 7 alpha-hydroxylase specific activities of 44 +/- 8% and 57 +/ - 3%, respectively (P < 0.03 and < 0.05). Similar changes were observe d in cholesterol 7 alpha-hyroxylase steady-state mRNA levels, which de creased by 43 +/- 10% (P < 0.001) and 56 +/- 19% (P < 0.05), respectiv ely. Cholesterol 7 alpha-hydroxylase transcriptional activity in A + T and H rats decreased by 34 +/- 11% (P < 0.01) and 61 +/- 4% (P < 0.00 1), respectively. The observed decreases were greater after H than aft er A + T, suggesting the possibility that another pituitary hormone pl ays a role in regulation of cholesterol 7 alpha-hydroxylase. Thyroidec tomy alone led to a decrease in cholesterol 7 alpha-hydroxylase specif ic activity of 37 +/- 7% (P < 0.05) and a trend toward decreased stead y-state mRNA levels (21 +/- 12%; P = ns). Adrenalectomy did not signif icantly decrease cholesterol 7 alpha-hydroxylase specific activity or mRNA levels. Neither thyroidectomy nor adrenalectomy alone affected tr anscriptional activity. We conclude that under physiologic circumstanc es, full expression of the cholesterol 7 alpha-hydroxylase gene requir es synergistic action of glucocorticoids and thyroid hormone.