title: 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.
abstract: 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.
authors.affiliation: Laboratory of Developmental Biology, Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Gullberg
authors.forename: M
authors.initials: M
authors.lastname: Rudling
authors.forename: D
authors.initials: D
authors.lastname: Forrest
authors.forename: B
authors.initials: B
authors.lastname: Angelin
authors.forename: B
authors.initials: B
authors.lastname: Vennström
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D002790:Cholesterol 7-alpha-Hydroxylase