Isosteviol protects free fatty acid- and high fat diet-induced hepatic injury via modulating PKC-β/p66Shc/ROS and ER stress pathways
Isosteviol protects free fatty acid- and high fat diet-induced hepatic injury via modulating PKC-β/p66Shc/ROS and ER stress pathways
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异甜菊醇通过调节 PKC-β/p66Shc/ROS 和 ER 应激途径保护游离脂肪酸和高脂肪饮食引起的肝损伤
DOI：
10.1089/ars.2018.7521
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发表时间：
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通讯作者：
Zhou Huiping
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文献类型：
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作者：
Yi Hongwei;Xu Deyi;Wu Xudong;Xu Fang;Lin Lin;Zhou Huiping
目的：非酒精性脂肪性肝病（NAFLD）是慢性肝病最常见的原因。然而，除了管理生活方式和控制饮食外，没有批准的药物治疗NAFLD。大量研究表明，游离脂肪酸（FFA）和高脂饮食（HFD）诱导的肝损伤涉及多种机制，包括线粒体功能障碍、氧化应激和内质网（ER）应激激活以及溶酶体功能障碍。先前的研究报道了异甜菊醇（ISV），一种甜菊苷的衍生物，可预防HFD诱导的肝损伤。结果：本研究采用体外原代大鼠肝细胞和在体NAFLD模型，探讨了ISV介导的抗FFA/HFD诱导的肝脂毒性作用的细胞/分子机制。结果表明，ISV通过诱导氧化应激和内质网应激来抑制FFA-/HFD诱导的肝损伤。具体而言，ISV抑制Src-同源性-2-结构域转化蛋白1（p66 Shc）的表达、活化和线粒体易位，所述Src-同源性-2-结构域转化蛋白1（p66 Shc）是介导氧化应激诱导的损伤的衔接蛋白，并且是蛋白激酶C-β（PKC-β）的底物，通过抑制PKC-β活性。而ISV对p66 Shc的肽基脯氨酰顺反异构酶、丝氨酸/苏氨酸蛋白磷酸酶2A、异构酶和磷酸化酶的表达和活性无影响。创新与结论：我们首次发现ISV通过调节PKC-β/p66 Shc/氧化途径和ER应激途径来预防FFA/HFD诱导的肝损伤。ISV是一种很有前途的NAFLD治疗药物。氧化还原信号。30，1949-1968.
Aims:Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress, and lysosome dysfunction. A previous study reported that Isosteviol (ISV), a derivative of stevioside, prevents HFD-induced hepatic injury. However, the underlying mechanisms remain unclear.Results:In this study, we examined the potential cellular/molecular mechanisms underlying ISV-mediated protective effect against FFA-/HFD-induced hepatic lipotoxicity by using bothin vitroprimary rat hepatocytes and thein vivorat NAFLD model. The results indicated that ISV inhibits FFA-/HFD-induced hepatic injuryviareducing oxidative and ER stress. Specifically, ISV inhibited the expression, activation, and mitochondrial translocation of Src-homology-2-domain-containing transforming protein 1 (p66Shc), an adapter protein that mediates oxidative stress-induced injury and is a substrate of protein kinase C-β (PKC-β),viainhibition of PKC-β activity. However, ISV had no effect on the expression and activity of peptidyl-prolyl cis-trans isomerase and serine/threonine protein phosphatase 2A, isomerase and phosphorylase of p66Shc. In addition, ISV also inhibited FFA-induced ER stress and decreased ER-mitochondrial interaction.Innovation and Conclusion:We first identified that ISV prevents FFA-/HFD-induced hepatic injury through modulating PKC-β/p66Shc/oxidative and ER stress pathways. ISV represents a promising therapeutic agent for NAFLD in the future.Antioxid. Redox Signal. 30, 1949–1968.