Inhibition of Thyroid Hormone Binding to the Nuclear Receptor by Mobilization of Free Fatty Acids

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 µM, 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 µM. While the plasma concentration of FFAs in total was 0.4 to 1 mM, their nuclear concentration was about 5 µM. 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.

Chromatin - Non-Esterified Fatty Acid - Norepinephrine - Oleic Acid - Triiodothyronine

References

• 1 Oppenheimer J H, Samuels H H (eds). Molecular Basis of Thyroid Hormone Action.  New York:; Academic Press, 1983
• 2 Dillmann W H. Biochemical basis of thyroid hormone action in the heart.  Am J Med. 1990;  88 626-630
• 3 Wu P S, Moriscot A S, Knowlton K U, Hilal-Dandan R, He H, Dillmann W H. Alpha1-adrenergic stimulation inhibits 3,5,3’-triiodothyronine induced expression of the rat heart sarcoplasmic reticulum Ca²⁺ adenosine triphosphatase gene.  Endocrinology. 1997;  138 114-120
• 4 Gloss B, Sayen M R, Trost S U, Bluhm W F, Meyer M, Swanson E A, Usala S J, Dillmann W H. Altered cardiac phenotype in transgenic mice carrying the delta337 threonine thyroid hormone receptor beta mutant derived from the S family.  Endocrinology. 1999;  140 897-902
• 5 Iritani N. Nutritional and hormonal regulation of lipogenic-enzyme gene expression in rat liver.  Eur J Biochem. 1992;  205 433-442
• 6 Gavino V C, Gavino G R. Adipose hormone-sensitive lipase preferentially releases polyunsaturated fatty acids from triglycerides.  Lipids. 1992;  27 950-954
• 7 Inoue A, Yamamoto N, Morisawa Y, Uchimoto T, Yukioka M, Morisawa S. Unesterified fatty acids inhibit thyroid hormone binding to the nuclear receptor.  Eur J Biochem. 1989;  183 565-572
• 8 Li Q, Yamamoto N, Inoue A, Morisawa S. Fatty acyl CoAs are potent inhibitors of the nuclear thyroid hormone receptor in vitro. .  J Biochem. 1990;  107 699-702
• 9 Li Q, Yamamoto N, Morisawa S, Inoue A. Fatty acyl-CoA binding activity of the nuclear thyroid hormone receptor.  J Cell Biochem. 1993;  52 1-7
• 10 Inoue A, Higashi Y, Hasuma T, Morisawa S, Yukioka M. A set of non-histone proteins isolated from the nuclei of various rat tissues.  Eur J Biochem. 1983;  35 61-68
• 11 Yamamoto N, Inoue A, Takahashi K P, Li Q, Nakamura H, Tagami T, Sasaki S, Imura H, Morisawa S. Loss of thyroid hormone receptor activity in primary cultured rat hepatocytes is reversed by 2-mercaptoethanol.  Biochem J. 1992;  281 669-673
• 12 Li Q, Inoue A. Preparation of unoccupied thyroid hormone receptor.  Biochem J. 1994;  297 75-78
• 13 van der Klis F R, Schmidt E D, van Beeren H C, Wiersinga W M. Competitive inhibition of T3 binding to alpha 1 and beta 1 thyroid hormone receptors by fatty acids.  Biochem Biophys Res Commun. 1991;  179 1011-1016
• 14 Schwartz H L, Lazer M A, Oppenheimer J H. Widespread distribution of immunoreactive thyroid hormone beta 2 receptor (TR beta 2) in the nuclei of extrapituitary rat tissues.  J Biol Chem. 1994;  269 24 777-24 782
• 15 Schaap F G, Hamers L, van der Vusse G J, Glatz J F. Molecular cloning of fatty acid-transport protein cDNA from rat.  Biochim Biophys Acta. 1997;  1354 29-34
• 16 Schaap F G, van der Vusse G J, Glatz J F. Fatty acid-binding proteins in the heart.  Mol Cell Biochem. 1998;  180 43-51
• 17 van der Vusse G J, Glatz J F, Stam H C, Reneman R S. Fatty acid homeostasis in the normoxic and ischemic heart.  Physiol Rev. 1992;  72 881-940