AUTHOR=Lin Suwen , Huang Shengjian , Deng Zhou , Zhang Yu , Huang Lin , Wu Yanyi , Lv Shuyan , Wang Zhiyi , Huang Ning , Wang Lan , Chen Ziqi , Yu Guangyin , Yin Weihua , Zhou You , Fang Zhengyu TITLE=Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders JOURNAL=Frontiers in Endocrinology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1109615 DOI=10.3389/fendo.2023.1109615 ISSN=1664-2392 ABSTRACT=Introduction

Thyroid hormone receptor β (THR-β) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-β agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo.

Methods

We conducted luciferase reporter gene assays to assess the activation of THR-β and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011.

Results

Compared with MGL-3196, CS271011 showed higher THR-β activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes.

Conclusions

CS271011 is a potent and liver-targeted THR-β agonist for treating lipid metabolism disorders.