AUTHOR=Zhao Xue , Cao Yedi , Jin Hongfang , Wang Xiuli , Zhang Lanbo , Zhang Yang , Yu Yang , Huang Youyuan , Gao Ying , Zhang Junqing 

TITLE=Hydrogen Sulfide Promotes Thyroid Hormone Synthesis and Secretion by Upregulating Sirtuin-1

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.838248

DOI=10.3389/fphar.2022.838248

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> One mechanism of hypothyroidism involves the disruption of thyroid hormone synthesis and secretion by thyrocytes. Hydrogen sulfide (H<sub>2</sub>S), 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 H<sub>2</sub>S promotes the synthesis and secretion of thyroid hormones by upregulating SIRT1.</p><p><bold>Methods:</bold> Real-time PCR and immunohistochemistry were used to detect the mRNA and protein expression of H<sub>2</sub>S-generating enzymes in normal human thyroid tissues. Serum H<sub>2</sub>S concentrations from hypothyroid patients (<italic>n</italic> = 32) and euthyroid participants (<italic>n</italic> = 41) were detected by H<sub>2</sub>S-selective sensors. Thirty-one Sprague–Dawley rats were divided into control group (<italic>n</italic> = 10), hypothyroid group (induced by MMI, <italic>n</italic> = 10) and hypothyroid + NaHS group (<italic>n</italic> = 11), and the FT4, TT4 and TSH levels were assayed. Human primary thyrocytes were incubated with H<sub>2</sub>S donor sodium hydrosulfide (NaHS) or NaHS plus SIRT1 inhibitor (EX527) <italic>in vitro</italic>. 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.</p><p><bold>Results:</bold> H<sub>2</sub>S levels in serum from hypothyroid patients were decreased compared to those from euthyroid participants (<italic>p</italic> &lt; .05), and serum H<sub>2</sub>S levels were positively correlated with FT3, FT4, TT3, and TT4 levels in all subjects (all <italic>p</italic> &lt; .0001). <italic>In vivo</italic>, NaHS promoted thyroid function in hypothyroid rats (<italic>p</italic> &lt; .05). <italic>In vitro</italic>, H<sub>2</sub>S was detected in supernatant, and <italic>CBS</italic> mRNA was higher than <italic>CSE</italic> and <italic>3-MPST</italic> in human primary thyrocytes (<italic>p</italic> &lt; .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 <italic>p</italic> &lt; .05).</p><p><bold>Conclusion:</bold> H<sub>2</sub>S is mainly generated in thyrocytes by CBS. Serum H<sub>2</sub>S levels are decreased with hypothyroidism. H<sub>2</sub>S promotes the synthesis and secretion of thyroid hormones and the expression of related molecules by upregulating SIRT1.</p>