Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease.
Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease.
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通过鼠尾草酸诱导的 miR-34a 抑制激活 SIRT1/p66shc 抗凋亡途径可保护大鼠免受非酒精性脂肪肝疾病的影响
DOI：
10.1038/cddis.2015.196
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发表时间：
2015-07-23
影响因子：
9
通讯作者：
Yao J
中科院分区：
文献类型：
--
作者：
Shan W;Gao L;Zeng W;Hu Y;Wang G;Li M;Zhou J;Ma X;Tian X;Yao J
最近的研究表明，miR-34 a表达显著上调，并与非酒精性脂肪性肝病（NAFLD）的细胞凋亡有关。鼠尾草酸（CA）是一种新型的抗氧化剂，在器官损伤（包括肝损伤）中是一种潜在的细胞凋亡抑制剂。本研究旨在探讨NAFLD中miR-34 a表达的信号转导机制以及CA的抗凋亡作用。CA处理显著降低了高脂饮食（HFD）诱导的转氨酶活性升高以及血清甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和丙二醛（MDA）水平，但升高了血清高密度脂蛋白胆固醇（HDL-C）和肝脏超氧化物歧化酶（SOD）水平。此外，CA治疗改善了由HFD暴露引起的裂解半胱天冬酶-3的增加，并完全逆转了HFD诱导的锰超氧化物歧化酶（MnSOD）和B细胞淋巴瘤超大表达的降低。CA还抵消了HFD或棕榈酸（PA）诱导的caspase-3和caspase-9活性的增加。从机制上讲，CA逆转了HFD或PA诱导的miR-34 a上调，这是SIRT 1的最佳特征调节剂。重要的是，miR-34 a表达的减少与SIRT 1/p66 shc通路的激活密切相关，SIRT 1/p66 shc通路可减弱肝脏缺血/再灌注损伤中的肝细胞凋亡。L02细胞中的双重荧光素酶测定验证了CA对SIRT 1的调节，这至少部分通过miR-34 a发生。此外，miR-34 a过表达被CA显著抵消，这阻止了miR-34 a依赖的SIRT 1/p66 shc通路的抑制和细胞凋亡。总的来说，我们的研究结果支持肝细胞凋亡和miR-34 a/SIRT 1/p66 shc通路之间的联系，这可以通过CA在NAFLD中进行调节。
Recent studies have demonstrated that miR-34a expression is significantly upregulated and associated with apoptosis in nonalcoholic fatty liver disease (NAFLD). Carnosic acid (CA) is a novel antioxidant and a potential inhibitor of apoptosis in organ injury, including liver injury. This study aimed to investigate the signaling mechanisms underlying miR-34a expression and the antiapoptotic effect of CA in NAFLD. CA treatment significantly reduced the high-fat diet (HFD)-induced elevations in aminotransferase activity as well as in serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and malondialdehyde (MDA) levels but increased serum high-density lipoprotein cholesterol (HDL-C) and hepatic superoxide dismutase (SOD) levels. Moreover, CA treatment ameliorated the increase in cleaved caspase-3 caused by HFD exposure and completely reversed the HFD-induced decreases in manganese superoxide dismutase (MnSOD) and B-cell lymphoma-extra large expression. CA also counteracted the HFD- or palmitic acid (PA)-induced increases in caspase-3 and caspase-9 activity. Mechanistically, CA reversed the HFD- or PA-induced upregulation of miR-34a, which is the best-characterized regulator of SIRT1. Importantly, the decrease in miR-34a expression was closely associated with the activation of the SIRT1/p66shc pathway, which attenuates hepatocyte apoptosis in liver ischemia/reperfusion injury. A dual luciferase assay in L02 cells validated the modulation of SIRT1 by CA, which occurs at least partly via miR-34a. In addition, miR-34a overexpression was significantly counteracted by CA, which prevented the miR-34a-dependent repression of the SIRT1/p66shc pathway and apoptosis. Collectively, our results support a link between liver cell apoptosis and the miR-34a/SIRT1/p66shc pathway, which can be modulated by CA in NAFLD.