Thyroid Hormone Receptor Beta-deficient Mice Show Complete Loss of the Normal Cholesterol 7alpha-hydroxylase (CYP7A) Response to Thyroid Hormone but Display Enhanced Resistance to Dietary Cholesterol

Thyroid hormone (T3) influences hepatic cholesterol metabolism, and previous studies have established an important role of this hormone in the regulation of cholesterol 7alpha-hydroxylase (CYP7A), the rate-limiting enzyme in the synthesis of bile acids. To evaluate the respective contribution of thyroid hormone receptors (TR) alpha1 and beta in this regulation, the responses to 2% dietary cholesterol and T3 were studied in TRalpha1 and TRbeta knockout mice under hypo- and hyperthyroid conditions. Our experiments show that the normal stimulation in CYP7A activity and mRNA level by T3 is lost in TRbeta-/- but not in TRalpha1-/-mice, identifying TRbeta as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient TRbeta-/- mice showed an augmented CYP7A response after challenge with dietary cholesterol, and these animals did not develop hypercholesterolemia to the extent as did wild-type (wt) controls. The latter results lend strong support to the concept that TRs may exert regulatory effects in vivo independent of T3.