Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway.
Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway.
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DOI：
10.1677/joe-09-0448
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发表时间：
2010-05
期刊：
影响因子：
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通讯作者：
Gereben B
中科院分区：
文献类型：
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作者：
Christoffolete MA;Doleschall M;Egri P;Liposits Z;Zavacki AM;Bianco AC;Gereben B
甲状腺激素受体（TR）和肝脏X受体（LXR）是脂质代谢的主要调节因子。值得注意的是，LXRα和LXRβ靶向缺失的小鼠对西方饮食诱导的肥胖具有抗性，并表现出甲状腺激素激活2型脱碘酶（D2）的异位肝脏表达。我们假设LXR/类维生素A X受体（RXR）信号传导抑制肝D2表达，并在HepG 2细胞中使用含有人DIO 2（hDIO 2）启动子的荧光素酶报告基因对此进行了研究。鉴于与哺乳动物相反，鸡肝脏通常表达D2，因此还研究了鸡DIO 2（cDIO 2）启动子。22（R）-OH-胆固醇以剂量依赖性方式（100 μM，约2倍）负调节hDIO 2，而它不能影响cDIO 2启动子。hDIO 2启动子中的截短确定了-901至-584 bp区域为负调控的关键区域。我们还研究了9-顺式视黄酸（9-cis RA），TR和LXR的异二聚体伴侣RXR的配体，是否可以调节hDIO 2启动子。值得注意的是，9-cis RA以剂量依赖性方式抑制hDIO 2荧光素酶报告基因（1 μM，约4倍），而失活突变体RXR的共表达消除了这种作用。然而，RXR同源二聚体不太可能介导hDIO 2的抑制，因为DR-1在−506 bp处的诱变不会干扰9-顺式RA介导的抑制。我们的数据表明，hDIO 2转录负调控22（R）-OH-胆固醇和9-顺式RA，这是一致的LXR/RXR参与。在体内，胆固醇/9-cis RA对D2介导的三碘甲状腺原氨酸（T3）产生的抑制可以起到反馈回路的作用，因为T3降低了肝脏胆固醇水平。
Thyroid hormone receptor (TR) and liver X-receptor (LXR) are the master regulators of lipid metabolism. Remarkably, a mouse with a targeted deletion of both LXRα and LXRβ is resistant to western diet-induced obesity, and exhibits ectopic liver expression of the thyroid hormone activating type 2 deiodinase (D2). We hypothesized that LXR/retinoid X-receptor (RXR) signaling inhibits hepatic D2 expression, and studied this using a luciferase reporter containing the human DIO2 (hDIO2) promoter in HepG2 cells. Given that, in contrast to mammals, the chicken liver normally expresses D2, the chicken DIO2 (cDIO2) promoter was also studied. 22(R)-OH-cholesterol negatively regulated hDIO2 in a dose-dependent manner (100 μM, approximately twofold), while it failed to affect the cDIO2 promoter. Truncations in the hDIO2 promoter identified the region −901 to −584 bp as critical for negative regulation. We also investigated if 9-cis retinoic acid (9-cis RA), the ligand for the heterodimeric partner of TR and LXR, RXR, could regulate the hDIO2 promoter. Notably, 9-cis RA repressed the hDIO2 luciferase reporter (1 μM, approximately fourfold) in a dose-dependent manner, while coexpression of an inactive mutant RXR abolished this effect. However, it is unlikely that RXR homodimers mediate the repression of hDIO2 since mutagenesis of a DR-1 at −506 bp did not interfere with 9-cis RA-mediated repression. Our data indicate that hDIO2 transcription is negatively regulated by both 22(R)-OH-cholesterol and 9-cis RA, which is consistent with LXR/RXR involvement. In vivo, the inhibition of D2-mediated tri-iodothyronine (T3) production by cholesterol/9-cis RA could function as a feedback loop, given that T3 decreases hepatic cholesterol levels.