Discovery of JND003 as a New Selective Estrogen-Related Receptor α Agonist Alleviating Nonalcoholic Fatty Liver Disease and Insulin Resistance.
Discovery of JND003 as a New Selective Estrogen-Related Receptor α Agonist Alleviating Nonalcoholic Fatty Liver Disease and Insulin Resistance.
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发现 JND003 作为一种新的选择性雌激素相关受体 α (ERRα) 激动剂，可缓解非酒精性脂肪肝疾病和胰岛素抵抗
DOI：
10.1021/acsbiomedchemau.1c00050
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发表时间：
2022-06-15
期刊：
影响因子：
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通讯作者：
Ding, Ke
中科院分区：
文献类型：
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作者：
Mao, Liufeng;Peng, Lijie;Ren, Xiaomei;Chu, Yi;Nie, Tao;Lin, Wanhua;Zhao, Xuemei;Libby, Andrew;Xu, Yong;Chang, Yu;Lei, Chong;Loomes, Kerry;Wang, Na;Liu, Jinsong;Levi, Moshe;Wu, Donghai;Hui, Xiaoyan;Ding, Ke
非酒精性脂肪肝疾病（NAFLD）是慢性肝疾病的最普遍形式之一，意外地与肝胰岛素抵抗和降低的脂肪酸氧化有关发现的第一个孤儿核受体，作为能量稳态的主调节器，通过控制葡萄糖和脂质代谢。潜在的和选择性的ERRα激动剂JND003（7）为在体外和体内的研究表明，化合物增强了下游靶基因的反式激活，这是通过改善胰岛素敏感性和脂肪肝症状来完成的，此外，治疗效果在Err-lko小鼠中完全消除了。可以用作用于管理代谢疾病的有趣药物选择。
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver diseases and is causally linked to hepatic insulin resistance and reduced fatty acid oxidation. Therapeutic treatments targeting both hepatic insulin resistance and lipid oxidative metabolism are considered as feasible strategies to alleviate this disease. Emerging evidence suggests Estrogen-Related Receptor alpha (ERRα), the first orphan nuclear receptor identified, as a master regulator in energy homeostasis by controlling glucose and lipid metabolism. Small molecules improving the functions of ERRα may provide a new option for management of NAFLD. In the present study, by using liver-specific Errα knockout mouse (Errα-LKO), we showed that liver-specific deletion of ERRα exacerbated diet-evoked fatty liver, hepatic and systemic insulin resistance in mice. A potent and selective ERRα agonist JND003 (7) was also discovered. In vitro and in vivo investigation demonstrated that the compound enhanced the transactivation of ERRα downstream target genes, which was accompanied by improved insulin sensitivity and fatty liver symptoms. Furthermore, the therapeutic effects were completely abolished in Errα-LKO mice, indicative of its on-target efficacy. Our study thus suggests that hepatic ERRα is a viable target for NAFLD and that ERRα agonist may serve as an intriguing pharmacological option for management of metabolic diseases.