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
Scientific Research Center, the First Affiliated Hospital of Guangdong Pharmaceutical University, Nonglinxi Road 19, Guangzhou, Guangdong, 510080, PR China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
ACS Bio Med Chem Au. 2022 Jun 15;2(3):282-296. doi: 10.1021/acsbiomedchemau.1c00050. Epub 2022 Jan 31.
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 knockout mouse (-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. and 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 -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.
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病形式之一，与肝脏胰岛素抵抗和脂肪酸氧化减少存在因果关联。针对肝脏胰岛素抵抗和脂质氧化代谢的治疗方法被认为是缓解该疾病的可行策略。新出现的证据表明，雌激素相关受体α（ERRα）作为首个被鉴定的孤儿核受体，通过控制葡萄糖和脂质代谢，在能量稳态中起主要调节作用。改善ERRα功能的小分子可能为NAFLD的治疗提供新选择。在本研究中，我们通过使用肝脏特异性敲除小鼠（-LKO）表明，肝脏特异性缺失ERRα会加剧饮食诱发的小鼠脂肪肝、肝脏和全身胰岛素抵抗。还发现了一种强效且选择性的ERRα激动剂JND003（7）。研究表明，该化合物增强了ERRα下游靶基因的反式激活，同时胰岛素敏感性和脂肪肝症状得到改善。此外，在-LKO小鼠中治疗效果完全消失，表明其具有靶向疗效。因此，我们的研究表明肝脏ERRα是NAFLD的一个可行靶点，ERRα激动剂可能是治疗代谢性疾病的一种有趣的药理学选择。
