MicroRNA-29a Suppresses CD36 to Ameliorate High Fat Diet-Induced Steatohepatitis and Liver Fibrosis in Mice
MicroRNA-29a Suppresses CD36 to Ameliorate High Fat Diet-Induced Steatohepatitis and Liver Fibrosis in Mice
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DOI：
10.3390/cells8101298
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发表时间：
2019-10-01
期刊：
影响因子：
6
通讯作者：
Huang, Ying-Hsien
中科院分区：
文献类型：
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作者：
Lin, Hung-Yu;Wang, Feng-Sheng;Huang, Ying-Hsien
MicroRNA-29(miR-29)已被证明在减轻肝损伤后的炎症和纤维化方面发挥关键作用。非酒精性脂肪性肝病(NAFLD)是由于过量饮酒以外的原因导致脂肪沉积(脂肪变性)在肝脏中发生，并与肝纤维化有关。在这项研究中，我们询问miR-29a是否可以减少实验性高脂饮食(HFD)诱导的小鼠肥胖和肝纤维化。我们对miR-29a转基因小鼠(miR-29aTg小鼠)和野生型仔鼠在HFD诱导的NAFLD中的表达进行了系统的分析。结果表明，miR-29a的增加不仅可以减轻HFD诱导的小鼠体重增加，而且还可以减轻小鼠皮下、内脏和肠道脂肪积聚和肝细胞脂肪变性。此外，与喂食HFD饮食的野生型(WT)小鼠相比，miR-29aTg小鼠的肝组织显示出弱的纤维化基质伴随着受影响组织内低纤维化胶原蛋白1α1的表达。MiR-29a信号的增强还导致肝组织中上皮间充质转化执行转录因子Snail、间充质标志物vientin以及促炎标志物IL6和mcp1的表达下调。同时，miR-29aTg-HFD小鼠肝脏中PPAR-γ、线粒体转录因子A TFAM和线粒体DNA含量显著低于WT-HFD小鼠。体外荧光素酶报告实验进一步证实miR-29a模拟转染法降低了脂肪酸转位酶CD36在HepG2细胞中的表达。结论：我们的数据为miR-29a改善HDF诱导的肥胖、肝细胞脂肪变性和纤维化提供了新的见解，并强调了miR-29a在NAFLD调节中的作用。
MicroRNA-29 (miR-29) has been shown to play a critical role in reducing inflammation and fibrosis following liver injury. Non-alcoholic fatty liver disease (NAFLD) occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use and is associated with liver fibrosis. In this study, we asked whether miR-29a could reduce experimental high fat diet (HFD)-induced obesity and liver fibrosis in mice. We performed systematical expression analyses of miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates subjected to HFD-induced NAFLD. The results demonstrated that increased miR-29a not only alleviated HFD-induced body weight gain but also subcutaneous, visceral, and intestinal fat accumulation and hepatocellular steatosis in mice. Furthermore, hepatic tissue in the miR-29aTg mice displayed a weak fibrotic matrix concomitant with low fibrotic collagen1 alpha 1 expression within the affected tissues compared to the wild-type (WT) mice fed the HFD diet. Increased miR-29a signaling also resulted in the downregulation of expression of the epithelial mesenchymal transition-executing transcription factor snail, mesenchymal markers vimentin, and such pro-inflammation markers as il6 and mcp1 within the liver tissue. Meanwhile, miR-29aTg-HFD mice exhibited significantly lower levels of peroxisome proliferator-activated receptor gamma (PPAR gamma), mitochondrial transcription factor A TFAM, and mitochondria DNA content in the liver than the WT-HFD mice. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced fatty acid translocase CD36 expression in HepG2 cells. Conclusion: Our data provide new insights that miR-29a can improve HDF-induced obesity, hepatocellular steatosis, and fibrosis, as well as highlight the role of miR-29a in regulation of NAFLD.