Honokiol acts as an AMPK complex agonist therapeutic in non-alcoholic fatty liver disease and metabolic syndrome.
Honokiol acts as an AMPK complex agonist therapeutic in non-alcoholic fatty liver disease and metabolic syndrome.
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DOI：
10.1186/s13020-023-00729-5
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发表时间：
2023-03-17
期刊：
影响因子：
4.9
通讯作者：
Zhang, Xiao-Jing
中科院分区：
文献类型：
--
作者：
Tian, Ruifeng;Yang, Jinjie;Wang, Xiaoming;Liu, Shuaiyang;Dong, Ruixiang;Wang, Zhenya;Yang, Zifeng;Zhang, Yingping;Cai, Zhiwei;Yang, Hailong;Hu, Yufeng;She, Zhi-Gang;Li, Hongliang;Zhou, Junjie;Zhang, Xiao-Jing
非酒精性脂肪肝（NAFLD）及其相关的代谢综合征已成为人类健康的主要威胁，但仍然需要有效和安全的药物来治疗这些疾病。在这里，我们的目的是确定潜在的候选药物NAFLD和潜在的分子机制。使用药物重新定位策略在脂质蓄积的体外肝细胞模型中筛选具有约3000种化合物的FDA批准的药物库，其中和诺昔康被鉴定为有效的抗NAFLD候选物。我们在多种体外和体内模型中系统地检查了和诺明在NAFLD和代谢综合征中的治疗作用。转录组学检查和生物素-链霉亲和素结合试验用于探索潜在的分子机制，并通过拯救实验证实。和诺平显著抑制代谢综合征和NAFLD进展，如通过改善肝脂肪变性、肝纤维化、脂肪炎症和胰岛素抵抗所证明的。从机制上讲，和厚朴的有益作用主要是通过AMPK激活。与传统的AMPK上游调节因子不同，和诺啡肽直接与AMPKγ1亚基结合，从而有力地激活AMPK信号。AMPKγ1的和厚朴酚结合位点的突变在很大程度上消除了和厚朴酚对NAFLD的保护能力。这些发现清楚地证明了honokaline在多种模型中的有益作用，并揭示了honokaline在NAFLD和代谢综合征中以前未被认识的信号传导机制。这项研究还为通过靶向AMPKγ1亚基介导的信号激活治疗代谢性疾病提供了新的见解。在线版本包含补充材料，可通过10.1186/s13020-023-00729-5获得。
Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms. A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments. Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPKγ1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPKγ1 largely abolished the protective capacity of honokiol against NAFLD. These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPKγ1 subunit-mediated signaling activation. The online version contains supplementary material available at 10.1186/s13020-023-00729-5.
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DOI：
10.1002/hep.31568
发表时间：
2021-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Lin Q;Huang Z;Cai G;Fan X;Yan X;Liu Z;Zhao Z;Li J;Li J;Shi H;Kong M;Zheng MH;Conklin DJ;Epstein PN;Wintergerst KA;Mohammadi M;Cai L;Li X;Li Y;Tan Y
通讯作者：
Tan Y
影响因子：
5
作者：
Liu, Hui;Luo, Wu;Liu, Jiazheng;Kang, Xincong;Yan, Jianming;Zhang, Tingting;Yang, Lan;Shen, Lu;Liu, Dongbo
通讯作者：
Liu, Dongbo
影响因子：
4.6
作者：
An, Hongying;Wang, Yu;He, Ling
通讯作者：
He, Ling
低剂量索拉非尼作为线粒体解偶联剂并改善非酒精性脂肪性肝炎
影响因子：
29
作者：
Jian, Chongshu;Fu, Jiajun;Cheng, Xu;Shen, Li-Jun;Ji, Yan-Xiao;Wang, Xiaoming;Pan, Shan;Tian, Han;Tian, Song;Liao, Rufang;Song, Kehan;Wang, Hai-Ping;Zhang, Xin;Wang, Yibin;Huang, Zan;She, Zhi-Gang;Zhang, Xiao-Jing;Zhu, Lihua;Li, Hongliang
通讯作者：
Li, Hongliang
影响因子：
29
作者：
Mottillo EP;Desjardins EM;Crane JD;Smith BK;Green AE;Ducommun S;Henriksen TI;Rebalka IA;Razi A;Sakamoto K;Scheele C;Kemp BE;Hawke TJ;Ortega J;Granneman JG;Steinberg GR
通讯作者：
Steinberg GR