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Molecular Endocrinology 14 (11): 1739-1749
Copyright © 2000 by The Endocrine Society

Thyroid Hormone Receptor ß-Deficient Mice Show Complete Loss of the Normal Cholesterol 7{alpha}-Hydroxylase (CYP7A) Response to Thyroid Hormone but Display Enhanced Resistance to Dietary Cholesterol

Hjalmar Gullberg, Mats Rudling, Douglas Forrest, Bo Angelin and Björn Vennström

Laboratory of Developmental Biology (H.G., B.V.) Department of Cell and Molecular Biology (CMB) Karolinska Institute S-171 77 Stockholm Sweden
Centers for Metabolism and Endocrinology and Nutrition and Toxicology (M.R., B.A.) Department of Medicine Karolinska Institute at Huddinge University Hospital S-141 86 Stockholm, Sweden
Department of Human Genetics (D.F.) Mount Sinai School of Medicine New York, New York 10029

Thyroid hormone (T3) influences hepatic cholesterol metabolism, and previous studies have established an important role of this hormone in the regulation 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) {alpha}1 and ß in this regulation, the responses to 2% dietary cholesterol and T3 were studied in TR{alpha}1 and TRß 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 TRß-/- but not in TR{alpha}1-/- mice, identifying TRß as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient TRß-/- 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.




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