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

H Gullberg, M Rudling, C Saltó, D Forrest… - Molecular …, 2002 - academic.oup.com
H Gullberg, M Rudling, C Saltó, D Forrest, B Angelin, B Vennström
Molecular Endocrinology, 2002academic.oup.com
T3 potently influences cholesterol metabolism through the nuclear thyroid hormone receptor
β (TRβ), the most abundant TR isoform in rodent liver. Here, we have tested if TRα1, when
expressed at increased levels from its normal locus, can replace TRβ in regulation of
cholesterol metabolism. By the use of TRα2−/− β−/− animals that overexpress hepatic TRα1
6-fold, a near normalization of the total amount of T3 binding receptors was achieved. These
mice are similar to TRβ−/− and TRα1−/− β−/− mice in that they fail to regulate cholesterol 7α …
Abstract
T3 potently influences cholesterol metabolism through the nuclear thyroid hormone receptor β (TRβ), the most abundant TR isoform in rodent liver. Here, we have tested if TRα1, when expressed at increased levels from its normal locus, can replace TRβ in regulation of cholesterol metabolism. By the use of TRα2−/−β−/− animals that overexpress hepatic TRα1 6-fold, a near normalization of the total amount of T3 binding receptors was achieved. These mice are similar to TRβ−/− and TRα1−/−β−/− mice in that they fail to regulate cholesterol 7α-hydroxylase expression properly, and that their serum cholesterol levels are unaffected by T3. Thus, hepatic overexpression of TRα1 cannot substitute for absence of TRβ, suggesting that the TRβ 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 TRβ is not general: T3 regulation of type I iodothyronine deiodinase and the low density lipoprotein receptor were partially rescued by TRα1 overexpression. These in vivo data show that TRβ is necessary for the effects of T3 on cholesterol metabolism. That TRα1 only in some instances can substitute for TRβ indicates that T3 regulation of physiological and molecular processes in the liver occurs in an isoform-specific fashion.
Oxford University Press