Brent Gregory A
Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.
Thyroid. 2023 Oct;33(10):1140-1149. doi: 10.1089/thy.2022.0636. Epub 2023 Aug 18.
Thyroid hormone (TH) has actions in every tissue of the body and is essential for normal development, as well as having important actions in the adult. The earliest markers of TH action that were identified and monitored clinically, even before TH could be measured in serum, included oxygen consumption, basal metabolic rate, serum cholesterol, and deep tendon reflex time. Cellular, rodent, amphibian, zebrafish, and human models have been used to study TH action. Early studies of the mechanism of TH action focused on saturable-specific triiodothyronine (T3) nuclear binding and direct actions of T3 that altered protein expression. Additional effects of TH were recognized on mitochondria, stimulation of ion transport, especially the sodium potassium ATPase, augmentation of adrenergic signaling, role as a neurotransmitter, and direct plasma membrane effects. The cloning of the thyroid hormone receptor (THR) genes in 1986 and report of the THR crystal structure in 1995 produced rapid progress in understanding the mechanism of TH nuclear action, as well as the development of modified THR ligands. These findings revealed nuances of TH signaling, including the role of nuclear receptor coactivators and corepressors, repression of positively stimulated genes by the unliganded receptor, THR isoform-specific actions of TRα (THRA) and TRβ (THRB), and THR binding DNA as a heterodimer with retinoid-x-receptor (RXR) for genes positively regulated by TH. The identification of genetic disorders of TH transport and signaling, especially Resistance to Thyroid Hormone (RTH) and monocarboxylate transporter 8 () defects, has been highly informative with respect to the mechanism of TH action. The impact of THR isoform, post-translational modifications, receptor cofactors, DNA response element, and selective TH tissue uptake, on TH action, have clinical implications for diagnosing and treating thyroid disease. Additionally, these findings have led to the development of novel TH and TH analogue therapies for metabolic, neurological, and cardiovascular diseases.
甲状腺激素（TH）对身体的每个组织都有作用，对正常发育至关重要，在成年人中也有重要作用。早在血清中能够检测到TH之前，临床上就已识别并监测到的TH作用的最早标志物包括耗氧量、基础代谢率、血清胆固醇和深部腱反射时间。细胞、啮齿动物、两栖动物、斑马鱼和人类模型已被用于研究TH的作用。早期对TH作用机制的研究集中在可饱和的特异性三碘甲状腺原氨酸（T3）核结合以及T3改变蛋白质表达的直接作用上。人们还认识到TH对线粒体有额外作用、刺激离子转运，尤其是钠钾ATP酶、增强肾上腺素能信号传导、作为神经递质的作用以及对质膜的直接作用。1986年甲状腺激素受体（THR）基因的克隆以及1995年THR晶体结构的报道，在理解TH核作用机制以及开发修饰的THR配体方面取得了迅速进展。这些发现揭示了TH信号传导的细微差别，包括核受体共激活因子和共抑制因子的作用、未结合配体的受体对正刺激基因的抑制、TRα（THRA）和TRβ（THRB）的THR亚型特异性作用，以及THR与视黄酸X受体（RXR）作为异二聚体结合DNA以调控TH正向调节的基因。TH转运和信号传导的遗传疾病的鉴定，尤其是甲状腺激素抵抗（RTH）和单羧酸转运体8（）缺陷，对于TH作用机制具有重要的指导意义。THR亚型、翻译后修饰、受体辅因子、DNA反应元件和选择性TH组织摄取对TH作用的影响，对甲状腺疾病的诊断和治疗具有临床意义。此外，这些发现还促成了针对代谢、神经和心血管疾病的新型TH和TH类似物疗法的开发。
