School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Outer Ring Road, Guangzhou, 510006, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China.
Nat Commun. 2020 Nov 16;11(1):5807. doi: 10.1038/s41467-020-19668-y.
Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.
慢性非酒精性脂肪性肝炎（NASH）是一种代谢紊乱疾病，常导致肝纤维化，而目前针对肝纤维化的治疗选择有限。脂联素是一种脂肪细胞因子，通过与受体 AdipoR1 和 AdipoR2 结合来调节葡萄糖和脂质代谢，并且已经报道 AdipoRs 信号可以增强脂肪酸氧化和葡萄糖摄取。在这里，我们合成并报告了一种基于脂联素的激动剂 JT003，它能够有效改善高脂肪饮食诱导的 NASH 小鼠的胰岛素抵抗，并抑制 CCl 诱导的肝纤维化中肝星状细胞（HSCs）的激活。机制研究表明，JT003 同时刺激 AdipoR1 和 AdipoR2 介导的信号通路以及 PI3K-Akt 通路。此外，JT003 治疗可显著改善内质网-线粒体轴功能，从而减少 HSCs 的激活。因此，AdipoR1/AdipoR2 双重激动剂改善了小鼠模型中的 NASH 和纤维化，为开发基于 AdipoRs 的肝纤维化治疗药物提供了药理学和生物学基础。
