Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis.
Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis.
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DOI：
10.1038/srep44754
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发表时间：
2017-03-17
影响因子：
4.6
通讯作者：
Ogawa Y
中科院分区：
文献类型：
--
作者：
Komiya C;Tanaka M;Tsuchiya K;Shimazu N;Mori K;Furuke S;Miyachi Y;Shiba K;Yamaguchi S;Ikeda K;Ochi K;Nakabayashi K;Hata KI;Itoh M;Suganami T;Ogawa Y
非酒精性脂肪性肝炎（NASH）的特征是脂肪变性伴小叶炎症和肝细胞损伤。吡非尼酮（PFD）是一种口服生物可利用的吡啶酮衍生物，已在临床上用于治疗特发性肺纤维化。然而，PFD是否改善具有人类NASH样表型的小鼠模型中的肝纤维化仍然未知。在这项研究中，我们采用黑素皮质素4受体缺陷（MC 4 R-KO）小鼠作为具有人类NASH样表型的小鼠模型，以阐明PFD对NASH发展的影响和作用机制。PFD显著减弱了西方饮食（WD）喂养的MC 4 R-KO小鼠的肝纤维化，而不影响代谢特征或脂肪变性。PFD可预防与WD喂养的MC 4 R-KO小鼠中肝细胞凋亡减少相关的肝损伤和纤维化。PFD预处理可抑制肿瘤坏死因子-α（TNF-α）诱导的野生型小鼠肝损伤和肝纤维化反应，并减少肝细胞凋亡。PFD还通过降低caspase-8和caspase-3的活化来防止TNF-α诱导的体外肝细胞凋亡。本研究为PFD在人NASH小鼠模型中的抗纤维化作用提供了证据。这项研究的数据突出了肝细胞凋亡作为一个潜在的治疗靶点，并表明PFD可以重新定位为人类NASH的抗纤维化药物。
Non-alcoholic steatohepatitis (NASH) is characterized by steatosis with lobular inflammation and hepatocyte injury. Pirfenidone (PFD) is an orally bioavailable pyridone derivative that has been clinically used for the treatment of idiopathic pulmonary fibrosis. However, it remains unknown whether PFD improves liver fibrosis in a mouse model with human NASH-like phenotypes. In this study, we employed melanocortin 4 receptor-deficient (MC4R-KO) mice as a mouse model with human NASH-like phenotypes to elucidate the effect and action mechanisms of PFD on the development of NASH. PFD markedly attenuated liver fibrosis in western diet (WD)-fed MC4R-KO mice without affecting metabolic profiles or steatosis. PFD prevented liver injury and fibrosis associated with decreased apoptosis of liver cells in WD-fed MC4R-KO mice. Pretreatment of PFD inhibited the tumor necrosis factor-α (TNF-α)-induced liver injury and fibrogenic responses associated with decreased apoptosis of liver cells in wild-type mice. PFD also prevented TNF-α-induced hepatocyte apoptosis in vitro with reduced activation of caspase-8 and -3. This study provides evidence for the antifibrotic effect of PFD in a mouse model of human NASH. The data of this study highlight hepatocyte apoptosis as a potential therapeutic target, and suggest that PFD can be repositioned as an antifibrotic drug for human NASH.