Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7 alpha-hydroxylase (CYP7A) response to thyroid hormone butdisplay enhanced resistance to dietary cholesterol

Thyroid hormone (T-3) influences hepatic cholesterol metabolism, and previo us studies have established an important role of this hormone in the regula tion of cholesterol 7 alpha -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 resp onses to 2% dietary cholesterol and T-3 were studied in TR alpha1 and TR be ta knockout mice under hypo- and hyperthyroid conditions. Our experiments s haw that the normal stimulation in CYP7A activity and mRNA level by T-3 is lost in TR beta-/- but not in TR alpha1-/- mice, identifying TR beta as the mediator of T-3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T-3-deficient TR be ta-/- 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 suppo rt to the concept that TRs may exert regulatory effects in vivo independent of T-3.