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Molecular Endocrinology, doi:10.1210/me.2002-0009
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Molecular Endocrinology 16 (8): 1767-1777
Copyright © 2002 by The Endocrine Society

Requirement for Thyroid Hormone Receptor ß in T3 Regulation of Cholesterol Metabolism in Mice

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

Department of Cell and Molecular Biology (H.G., C.S., B.V.), 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; and Department of Human Genetics (D.F.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Björn Vennström, Department of Cell and Molecular Biology, Karolinska Institute, Room D427 Doktorsringen 2D, Solna, Sweden S-171 77. E-mail: bjorn.vennstrom{at}cmb.ki.se.

T3 potently influences cholesterol metabolism through the nuclear thyroid hormone receptor ß (TRß), the most abundant TR isoform in rodent liver. Here, we have tested if TR{alpha}1, when expressed at increased levels from its normal locus, can replace TRß in regulation of cholesterol metabolism. By the use of TR{alpha}2-/-ß-/- animals that overexpress hepatic TR{alpha}1 6-fold, a near normalization of the total amount of T3 binding receptors was achieved. These mice are similar to TRß-/- and TR{alpha}1-/-ß-/- mice in that they fail to regulate cholesterol 7{alpha}-hydroxylase expression properly, and that their serum cholesterol levels are unaffected by T3. Thus, hepatic overexpression of TR{alpha}1 cannot substitute for absence of TRß, suggesting that the TRß gene has a unique role in T3 regulation of cholesterol metabolism in mice. However, examination of T3 regulation of hepatic target genes revealed that dependence on TRß is not general: T3 regulation of type I iodothyronine deiodinase and the low density lipoprotein receptor were partially rescued by TR{alpha}1 overexpression. These in vivo data show that TRß is necessary for the effects of T3 on cholesterol metabolism. That TR{alpha}1 only in some instances can substitute for TRß indicates that T3 regulation of physiological and molecular processes in the liver occurs in an isoform-specific fashion.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ
Ligands:   Thyroid hormone



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