Zhao Xue, Cao Yedi, Jin Hongfang, Wang Xiuli, Zhang Lanbo, Zhang Yang, Yu Yang, Huang Youyuan, Gao Ying, Zhang Junqing
Department of Endocrinology, Peking University First Hospital, Beijing, China.
Department of Pediatrics, Peking University First Hospital, Beijing, China.
Front Pharmacol. 2022 Feb 10;13:838248. doi: 10.3389/fphar.2022.838248. eCollection 2022.
One mechanism of hypothyroidism involves the disruption of thyroid hormone synthesis and secretion by thyrocytes. Hydrogen sulfide (HS), as a gas signaling molecule, participates in many physiopathologic processes by upregulating sirtuin-1 (SIRT1). The aim of the current study was to explore whether HS promotes the synthesis and secretion of thyroid hormones by upregulating SIRT1. Real-time PCR and immunohistochemistry were used to detect the mRNA and protein expression of HS-generating enzymes in normal human thyroid tissues. Serum HS concentrations from hypothyroid patients ( = 32) and euthyroid participants ( = 41) were detected by HS-selective sensors. Thirty-one Sprague-Dawley rats were divided into control group ( = 10), hypothyroid group (induced by MMI, = 10) and hypothyroid + NaHS group ( = 11), and the FT4, TT4 and TSH levels were assayed. Human primary thyrocytes were incubated with HS donor sodium hydrosulfide (NaHS) or NaHS plus SIRT1 inhibitor (EX527) . Thyroid hormone synthesis- and secretion-related proteins [thyroid peroxidase (TPO), sodium iodide transporter (NIS), Pendrin, monocarboxylic acid transporter 8 (MCT8)] were analyzed by real-time PCR and Western blot. HS levels in serum from hypothyroid patients were decreased compared to those from euthyroid participants ( < .05), and serum HS levels were positively correlated with FT3, FT4, TT3, and TT4 levels in all subjects (all < .0001). , NaHS promoted thyroid function in hypothyroid rats ( < .05). , HS was detected in supernatant, and mRNA was higher than and in human primary thyrocytes ( < .05). The protein levels of TPO, NIS, Pendrin and MCT8 were upregulated in a concentration-dependent manner for NaHS in thyrocytes. After blocking SIRT1 with EX527, we found that the increasing levels of TPO, NIS, Pendrin, and MCT8 and TPO activity were downregulated in thyrocytes incubated with NaHS, and FT4 levels in the cell supernatant were also decreased significantly (all < .05). HS is mainly generated in thyrocytes by CBS. Serum HS levels are decreased with hypothyroidism. HS promotes the synthesis and secretion of thyroid hormones and the expression of related molecules by upregulating SIRT1.
甲状腺功能减退的一种机制涉及甲状腺细胞对甲状腺激素合成和分泌的破坏。硫化氢（HS）作为一种气体信号分子，通过上调沉默调节蛋白1（SIRT1）参与许多生理病理过程。本研究的目的是探讨HS是否通过上调SIRT1来促进甲状腺激素的合成和分泌。采用实时定量聚合酶链反应（Real-time PCR）和免疫组织化学方法检测正常人甲状腺组织中HS生成酶的mRNA和蛋白表达。使用HS选择性传感器检测甲状腺功能减退患者（n = 32）和甲状腺功能正常参与者（n = 41）的血清HS浓度。将31只Sprague-Dawley大鼠分为对照组（n = 10）、甲状腺功能减退组（由甲巯咪唑诱导，n = 10）和甲状腺功能减退+硫氢化钠（NaHS）组（n = 11），并检测游离甲状腺素（FT4）、总甲状腺素（TT4）和促甲状腺激素（TSH）水平。将人原代甲状腺细胞与HS供体硫氢化钠（NaHS）或NaHS加SIRT1抑制剂（EX527）孵育。通过实时定量聚合酶链反应和蛋白质免疫印迹法分析甲状腺激素合成和分泌相关蛋白[甲状腺过氧化物酶（TPO）、碘化钠转运体（NIS）、pendrin、单羧酸转运体8（MCT8）]。与甲状腺功能正常参与者相比，甲状腺功能减退患者血清中的HS水平降低（P < 0.05），且所有受试者血清HS水平与FT3、FT4、TT3和TT4水平呈正相关（均P < 0.0001）。此外，NaHS可改善甲状腺功能减退大鼠的甲状腺功能（P < 0.05）。并且，在人原代甲状腺细胞的上清液中检测到HS，且CBS mRNA高于CSE和3-MST mRNA（P < 0.05）。在甲状腺细胞中，NaHS可使TPO、NIS、pendrin和MCT8的蛋白水平呈浓度依赖性上调。用EX527阻断SIRT1后，我们发现，在与NaHS孵育的甲状腺细胞中，TPO、NIS、pendrin和MCT8水平升高以及TPO活性上调均受到抑制，且细胞上清液中的FT4水平也显著降低（均P < 0.05）。HS主要由甲状腺细胞中的CBS产生。甲状腺功能减退时血清HS水平降低。HS通过上调SIRT1促进甲状腺激素的合成和分泌以及相关分子的表达。
