Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model
Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model
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DOI：
10.1074/jbc.m507877200
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发表时间：
2006-01-06
影响因子：
4.8
通讯作者：
Wondisford, FE
中科院分区：
文献类型：
--
作者：
Hashimoto, K;Cohen, RN;Wondisford, FE
高胆固醇血症见于甲状腺功能减退和甲状腺激素抵抗的患者。在这项研究中，我们研究了甲状腺激素受体β（TR-β）突变小鼠模型的甲状腺激素抵抗的胆固醇代谢。尽管已经在TR-β敲除小鼠中报道了胆固醇代谢的研究，但是在该敲入模型中非配体结合TR-β蛋白的一般化表达更完全地再现了甲状腺功能减退状态，因为TR的甲状腺功能减退作用是由未配体受体介导的。在甲状腺功能减退状态下，高胆固醇饮食增加了野生型动物（WT）的血清胆固醇水平，但相对于单独的甲状腺功能减退，突变型（MUT）小鼠的血清胆固醇水平没有变化或降低。7 α-羟化酶（CYP 7A 1）是胆固醇代谢的限速酶，在所有动物的甲状腺功能减退状态下均检测不到mRNA水平。三碘甲腺原氨酸替代恢复了WT小鼠中的CYP 7A 1 mRNA水平，但在MUT小鼠中的影响极小。相比之下，高胆固醇饮食显着诱导CYP 7A 1水平的MUT，但不是WT小鼠甲状腺功能减退症的状态。MUT动物中CYP 7A 1 mRNA水平升高和肝脏胆固醇含量降低可能是由于TR-β和肝脏X受体α（LXR-α）之间的相互作用，两者均与CYP 7A 1启动子中的直接重复+4（DR+4）元件结合。在转染研究中，WT而不是MUT TR-β拮抗LXR-α对该启动子的诱导。电迁移率变化分析显示，LXR/RXR异二聚体在MUT而不是WT TR-β存在下结合DR+4元件。提出了TR-β和LXR-α之间的串扰和潜在拮抗作用的机制。
Hypercholesterolemia is found in patients with hypothyroidism and resistance to thyroid hormone. In this study, we examined cholesterol metabolism in a thyroid hormone receptor beta ( TR-beta) mutant mouse model of resistance to thyroid hormone. Whereas studies of cholesterol metabolism have been reported in TR-beta knock-out mice, generalized expression of a non-ligand binding TR-beta protein in this knock-in model more fully recapitulates the hypothyroid state, because the hypothyroid effect of TRs is mediated by the unliganded receptor. In the hypothyroid state, a high cholesterol diet increased serum cholesterol levels in wild-type animals (WT) but either did not change or reduced levels in mutant (MUT) mice relative to hypothyroidism alone. 7 alpha-Hydroxylase (CYP7A1) is the rate-limiting enzyme in cholesterol metabolism and mRNA levels were undetectable in the hypothyroid state in all animals. triiodothyronine replacement restored CYP7A1 mRNA levels in WT mice but had minimal effect in MUT mice. In contrast, a high cholesterol diet markedly induced CYP7A1 levels in MUT but not WT mice in the hypothyroid state. Elevation of CYP7A1 mRNA levels and reduced hepatic cholesterol content in MUT animals are likely because of cross-talk between TR-beta and liver X receptor alpha(LXR-alpha), which both bind to a direct repeat +4 ( DR+4) element in the CYP7A1 promoter. In transfection studies, WT but not MUT TR-beta antagonized induction of this promoter by LXR-alpha. Electromobility shift analysis revealed that LXR/RXR heterodimers bound to the DR+4 element in the presence of MUT but not WT TR-beta. A mechanism for cross-talk, and potential antagonism, between TR-beta and LXR-alpha is proposed.