MicroRNA-30b regulates insulin sensitivity by targeting SERCA2b in non-alcoholic fatty liver disease
MicroRNA-30b regulates insulin sensitivity by targeting SERCA2b in non-alcoholic fatty liver disease
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MicroRNA™30b 通过靶向 SERCA2b 在非酒精性脂肪肝中调节胰岛素敏感性
DOI：
10.1111/liv.14067
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发表时间：
2019-08-01
影响因子：
6.7
通讯作者：
Zou, Cheng-Gang
中科院分区：
文献类型：
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作者：
Dai, Li-Li;Li, Shu-De;Zou, Cheng-Gang
背景与目的胰岛素抵抗与非酒精性脂肪性肝病密切相关，非酒精性脂肪性肝病是一种慢性、肥胖相关的肝病。内质网（ER）应激增加在胰岛素抵抗的发展中起重要作用。在这项研究中，我们研究了miRNAs在调节肥胖大鼠肝脏ER应激中的作用。方法采用miRNA芯片技术检测高脂饮食（HFD）大鼠肝脏中miRNA的表达谱。我们使用预测算法和荧光素酶报告基因测定来识别miRNAs的靶基因。通过尾静脉注射含有PGLV 3-miR-30 b或PGLV 3-miR-30 b antimiR的慢病毒颗粒以过表达miR-30 b或抑制miR-30 b。在人类受试者中使用瞬时弹性成像测量肝脂肪变性。结果miR-30 b在HFD处理的大鼠肝脏中表达显著上调。生物信息学和体外和体内研究使我们鉴定出肌浆网Ca 2 +-ATP酶2b（SERCA 2b）作为miR-30 b的新靶点。在正常饮食喂养的大鼠中，过表达miR-30 b可诱导ER应激和胰岛素抵抗，而在HFD处理的大鼠中，通过miR-30 b antimiR抑制miR-30 b可抑制ER应激和胰岛素抵抗。最后，我们的数据表明，在人类受试者中，血清miR-30 b水平与肝脏脂肪变性或胰岛素抵抗的稳态模型评估（HOMA-IR）之间存在正相关性。结论miR-30 b不仅是治疗胰岛素抵抗的潜在靶点，也是NAFLD的非侵袭性疾病生物标志物。
Background & Aims Insulin resistance is strongly associated with non-alcoholic fatty liver disease, a chronic, obesity-related liver disease. Increased endoplasmic reticulum (ER) stress plays an important role in the development of insulin resistance. In this study, we investigated the roles of miRNAs in regulating ER stress in the liver of rats with obesity. Methods We used miRNA microarray to determine the miRNA expression profiles in the liver of rats fed with a high fat diet (HFD). We used prediction algorithms and luciferase reporter assay to identify the target gene of miRNAs. To overexpress the miRNA miR-30b or inhibit miR-30b rats were injected with lentivirus particles containing PGLV3-miR-30b or PGLV3-miR-30b antimiR through tail vein. Hepatic steatosis was measured using transient elastography in human subjects. Results Our data showed that miR-30b was markedly up-regulated in the liver of HFD-treated rats. Bioinformatic and in vitro and in vivo studies led us to identify sarco(endo)plasmic reticulum Ca2+-ATPase 2b (SERCA2b), as a novel target of miR-30b. Overexpression of miR-30b induced ER stress and insulin resistance in rats fed with normal diet, whereas inhibition of miR-30b by miR-30b antimiR suppressed ER stress and insulin resistance in HFD-treated rats. Finally, our data demonstrated that there was a positive correlation between serum miR-30b levels and hepatic steatosis or homoeostasis model assessment of insulin resistance (HOMA-IR) in human subjects. Conclusions Our findings suggest that miR-30b represents not only a potential target for the treatment of insulin resistance, but also a non-invasive disease biomarker of NAFLD.