Bagga Anish D, Johnson Brian P, Zhang Qiang
Emory College of Arts and Sciences, Emory University, Atlanta, GA, 30322, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
Pflugers Arch. 2025 Mar;477(3):453-478. doi: 10.1007/s00424-024-03060-6. Epub 2025 Jan 3.
Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings. (1) Contrary to postulations that TTR and/or ALB are the major local T4 contributors, the three THBPs may unload comparable amounts of T4 in Liver, a rapidly perfused organ; however, their contributions in slowly perfused tissues follow the order of abundances of T4TBG, T4TTR, and T4ALB. The T3 amounts unloaded from or loaded onto THBPs in a tissue acting as a T3 sink or source respectively follow the order of abundance of T3TBG, T3ALB, and T3TTR regardless of perfusion rate. (2) Any THBP alone is sufficient to maintain spatially uniform TH tissue distributions. (3) The TH amounts unloaded by each THBP species are spatially dependent and nonlinear in a tissue, with ALB being the dominant contributor near the arterial end but conceding to TBG near the venous end. (4) Spatial gradients of TH transporters and metabolic enzymes may modulate these contributions, producing spatially invariant or heterogeneous TH tissue concentrations depending on whether the blood-tissue TH exchange operates in near-equilibrium mode. In summary, our modeling provides novel insights into the differential roles of THBPs in local TH tissue distribution.
血浆甲状腺激素（TH）结合蛋白（THBP），包括甲状腺素结合球蛋白（TBG）、转甲状腺素蛋白（TTR）和白蛋白（ALB），将甲状腺激素转运到甲状腺外部位，在那里甲状腺激素被局部卸载，然后通过膜转运体被吸收到组织本身。THBP在为组织摄取提供甲状腺激素方面的各自作用尚未完全明确。为了研究这一点，我们开发了一种甲状腺激素的空间人体生理动力学（PBK）模型，该模型产生了几个新的发现。（1）与认为TTR和/或ALB是主要局部T4贡献者的假设相反，这三种THBP在肝脏（一个快速灌注的器官）中可能卸载相当数量的T4；然而，它们在缓慢灌注组织中的贡献遵循T4-TBG、T4-TTR和T4-ALB丰度的顺序。从作为T3汇或源的组织中分别卸载到THBP上或从THBP上加载的T3量，无论灌注速率如何，都遵循T3-TBG、T3-ALB和T3-TTR丰度的顺序。（2）任何一种THBP单独就足以维持甲状腺激素在组织中的空间均匀分布。（3）每种THBP物种卸载的甲状腺激素量在组织中是空间依赖性的且是非线性的，白蛋白在动脉端附近是主要贡献者，但在静脉端附近让位于TBG。（4）甲状腺激素转运体和代谢酶的空间梯度可能会调节这些贡献，根据血液-组织甲状腺激素交换是否以近平衡模式运行，产生空间不变或异质的甲状腺激素组织浓度。总之，我们的模型为THBP在局部甲状腺激素组织分布中的不同作用提供了新的见解。
