Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice.
Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice.
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DOI：
10.1002/jbt.22876
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发表时间：
2021-10
影响因子：
3.6
通讯作者：
Cortopassi, Gino
中科院分区：
文献类型：
--
作者：
Jiang, Joy X.;Tomilov, Alexey;Montgomery, Claire;Hui, Chun Kui;Torok, Natalie J.;Cortopassi, Gino
SHc在人非酒精性脂肪性肝炎(NASH)肝脏中的表达增加，Shc缺陷的小鼠受到NASH的保护，因此抑制Shc可能成为治疗NASH的新策略。艾地苯酮最近被确认为第一个小分子Shc抑制剂药物。我们在肝纤维化蛋氨酸-胆碱缺乏(MCD)饮食和代谢性快餐饮食(FFD)NASH小鼠模型中测试了艾地苯酮。在纤维化的MCD NASH模型中，艾地苯酮减少了外周血单个核细胞Shc的表达和磷酸化，降低了肝脏Shc的表达，降低了血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶的水平，并通过定量聚合酶链式反应(QPCR)和羟脯氨酸定量观察到减轻了肝纤维化。在代谢性FFD模型中，艾地苯酮给药改善了胰岛素抵抗，并减少了定量聚合酶链式反应、羟脯氨酸测量和组织学显示的炎症和纤维化。因此，艾地苯酮改善了两种小鼠模型的NASH。作为一种安全无害的获批药物，艾德贝农可能是一种合理的人类NASH疗法。
Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH–thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and the metabolic fast food diet (FFD) mouse models of NASH. In the fibrotic MCD NASH model, idebenone reduced Shc expression and phosphorylation in peripheral blood mononuclear cells and Shc expression in the liver; decreased serum alanine aminotransferase and aspartate aminotransferase; and attenuated liver fibrosis as observed by quantitative polymerase chain reaction (qPCR) and hydroxyproline quantification. In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology. Thus, idebenone ameliorates NASH in two mouse models. As an approved drug with a benign safety profile, Idebenone could be a reasonable human NASH therapy.
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影响因子：
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作者：
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影响因子：
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DOI：
10.1152/ajpgi.00145.2011
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