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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cholesterol / blood
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Cholesterol / metabolism
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Cholesterol 7-alpha-Hydroxylase / drug effects
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Cholesterol 7-alpha-Hydroxylase / metabolism*
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Cholesterol, Dietary / pharmacology*
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DNA-Binding Proteins
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Hydroxymethylglutaryl CoA Reductases / genetics
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Hydroxymethylglutaryl CoA Reductases / metabolism
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Hypercholesterolemia / chemically induced
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Hypercholesterolemia / genetics
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Iodide Peroxidase / genetics
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Iodide Peroxidase / metabolism
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Lipoproteins, HDL / blood
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Lipoproteins, LDL / blood
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Liver / metabolism
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Liver X Receptors
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Male
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Mice
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Mice, Knockout
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Thyroid Hormone / genetics*
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Thyroid Hormones / metabolism
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Thyroid Hormones / pharmacology*
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Triiodothyronine / metabolism
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Triiodothyronine / pharmacology
Substances
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Cholesterol, Dietary
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DNA-Binding Proteins
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Lipoproteins, HDL
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Lipoproteins, LDL
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Liver X Receptors
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Receptors, Thyroid Hormone
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Thyroid Hormones
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Triiodothyronine
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Cholesterol
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Hydroxymethylglutaryl CoA Reductases
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iodothyronine deiodinase type I
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Iodide Peroxidase
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Cholesterol 7-alpha-Hydroxylase