Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.
Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.
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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
DOI：
10.1016/j.cmet.2020.04.011
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发表时间：
2020-05-05
期刊：
影响因子：
29
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
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
非酒精性脂肪性肝炎（NASH）正在成为肝细胞癌（HCC）的主要原因之一。索拉非尼是治疗晚期HCC的唯一一线药物，尽管其有严重的不良反应。在这里，我们报告说，在相当于大约十分之一的HCC临床剂量下，索拉非尼治疗有效地防止了小鼠和猴NASH的进展，没有观察到任何显著的不良事件。从机制上讲，索拉非尼在NASH中的益处不依赖于其在HCC中的经典激酶靶点，但涉及诱导轻度线粒体解偶联和随后的AMP活化蛋白激酶（AMPK）活化。总的来说，我们的研究结果证明了低剂量索拉非尼治疗NASH的治疗效果和信号传导机制。我们设想，这种新的NASH治疗策略有可能转化为有益的抗NASH治疗，其不良事件比目前在HCC中使用该药物时观察到的更少。Jian等人表明，低剂量索拉非尼安全有效地抑制了小鼠和猴的NASH进展。从机制上讲，诱导线粒体解偶联和随后的AMPK活化主要是索拉非尼在NASH中的治疗作用的基础。
Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib’s benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP–activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug’s current use in HCC. Jian et al. show that low-dose sorafenib safely and effectively suppressed NASH progression in both mice and monkeys. Mechanistically, induction of mitochondrial uncoupling and subsequent AMPK activation primarily underlies the therapeutic effects of sorafenib in NASH.
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影响因子：
12.8
作者：
Jeon SM
通讯作者：
Jeon SM
影响因子：
2.4
作者：
Kishida N;Matsuda S;Itano O;Shinoda M;Kitago M;Yagi H;Abe Y;Hibi T;Masugi Y;Aiura K;Sakamoto M;Kitagawa Y
通讯作者：
Kitagawa Y
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
影响因子：
4.1
作者：
Brand, MD;Pakay, JL;Cornwall, EJ
通讯作者：
Cornwall, EJ
影响因子：
13.5
作者：
Heimbach, Julie K.;Kulik, Laura M.;Marrero, Jorge A.
通讯作者：
Marrero, Jorge A.