Document Detail

Inhibition of thyroid hormone binding to the nuclear receptor by mobilization of free fatty acids.
MedLine Citation:
PMID:  11355745     Owner:  NLM     Status:  MEDLINE    
Through binding to its nuclear receptor (TR), thyroid hormone (T3) activates the expression of the thyroid hormone-responsive genes that are essential for the regulation of energy consumption. Previously, we found that free fatty acids (FFAs) and their CoA esters strongly inhibited the binding of T3 to its nuclear receptor in vitro. In the present study, we have examined the physiological relevance of this inhibitory mechanism. TRs in isolated nuclei and in a solubilized free form were half-maximally inhibited with oleic acid at 120 and 2.8 microM, respectively. The lower sensitivity of the nuclear TR as compared with free TR was attributed to the nuclear envelope and the association of TR with chromatin. Among TRs in chromatin, those in the transcriptionally active chromatin exhibited the highest sensitivities to FFAs and were inhibited half-maximally by oleic acid at 10 microM. While the plasma concentration of FFAs in total was 0.4 to 1 mM, their nuclear concentration was about 5 microM. Thus, the sensitivities of TRs in active chromatin and in solubilized form were at physiological levels with respect to the nuclear FFA concentration. We further examined the effect of FFA mobilization on the T3-binding to TR in animals. Nuclear T3-binding was significantly inhibited when plasma and cellular FFAs were increased by norepinephrine in vivo. The increase in cellular FFAs and the TR-inhibition were well correlated, and much larger in the heart than in the liver and kidney. These results suggest that TR is negatively controlled by increased FFAs in a tissue-dependent manner.
N Yamamoto; Q L Li; S Mita; S Morisawa; A Inoue
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme     Volume:  33     ISSN:  0018-5043     ISO Abbreviation:  Horm. Metab. Res.     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-05-17     Completed Date:  2001-09-13     Revised Date:  2009-02-19    
Medline Journal Info:
Nlm Unique ID:  0177722     Medline TA:  Horm Metab Res     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  131-7     Citation Subset:  IM    
Department of Biochemistry, Osaka City University Medical School, Osaka, Japan.
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MeSH Terms
Cell Nucleus / metabolism*
Chromatin / chemistry
Fatty Acids, Nonesterified / metabolism,  pharmacology*
Myocardium / metabolism
Norepinephrine / pharmacology
Rats, Wistar
Receptors, Thyroid Hormone / drug effects*,  metabolism
Triiodothyronine / metabolism*
Reg. No./Substance:
0/Chromatin; 0/Fatty Acids, Nonesterified; 0/Receptors, Thyroid Hormone; 51-41-2/Norepinephrine; 6893-02-3/Triiodothyronine

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