miR199a-5p inhibits hepatic insulin sensitivity via suppression of ATG14-mediated autophagy.
miR199a-5p inhibits hepatic insulin sensitivity via suppression of ATG14-mediated autophagy.
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miR199a-5p 通过抑制 ATG14 介导的自噬抑制肝脏胰岛素敏感性
DOI：
10.1038/s41419-018-0439-7
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发表时间：
2018-03-14
影响因子：
9
通讯作者：
Su Q
中科院分区：
文献类型：
--
作者：
Li B;Wu X;Chen H;Zhuang C;Zhang Z;Yao S;Cai D;Ning G;Su Q
众所周知，MicroRNAs （miRNAs）与包括糖尿病在内的许多代谢疾病有关。在这项研究中，我们研究了miR199a-5p在肝脏胰岛素敏感性调节中的作用。将Ad-anti-miR199a-5p腺病毒注射到饲喂高脂肪饮食的雄性C57BL/6J WT小鼠体内，以抑制miR199a-5p的表达，然后评估血糖水平和胰岛素抵抗。同样，将Ad-miR199a-5p腺病毒注射到雄性C57BL/6J WT小鼠体内，引起miR199a-5p过表达。为了研究自噬相关蛋白14 （ATG14）和miR199a-5p在胰岛素敏感性调节中的作用，我们在进行功能分析之前，将Ad-ATG14病毒或不含Ad-miR199a-5p注射到WT C57BL/6J小鼠体内。此外，我们用Ad-anti-miR199a-5p或Ad-miR199a-5p病毒感染HepG2细胞或原代肝细胞，以确定miR199a-5p对体外胰岛素抵抗的影响。最后，我们通过检测糖尿病患者肝脏样本中miR199a-5p的表达水平，探讨了miR199a-5p的临床相关性。我们首先证明，在体内敲低miR199a-5p会导致葡萄糖耐量和清除率降低，而miR199a-5p的过表达则会产生相反的效果。我们进一步确定了ATG14是miR199a-5p的靶点，ATG14部分挽救了miR199a-5p增强的葡萄糖和胰岛素耐受。此外，ATG14、LC3和BECLIN1的透射电镜和western blot数据表明，miR199a-5p通过ATG14调控自噬。在原代肝细胞和HepG2细胞中，miR199a-5p的下调抑制了胰岛素刺激下胰岛素受体β、糖原合成酶激酶3β和蛋白激酶B的磷酸化，而miR199a-5p的过表达进一步增强了它们的磷酸化。最后，我们在糖尿病患者的肝脏样本中检测到miR199a-5p水平上调，这与ATG14 mRNA水平降低和自噬水平下调相关。我们的研究揭示了miR199a-5p通过atg14介导的自噬调节肝脏胰岛素敏感性的新生物学作用。
MicroRNAs (miRNAs) are known to contribute to many metabolic diseases, including diabetes. In this study, we investigated the role of miR199a-5p in the regulation of hepatic insulin sensitivity. Ad-anti-miR199a-5p adenoviruses were injected into male C57BL/6J WT mice fed a high-fat diet to inhibit miR199a-5p expression before the glucose levels and insulin resistance were assessed. Similarly, Ad-miR199a-5p adenoviruses were injected into male C57BL/6J WT mice to cause the overexpression of miR199a-5p. To investigate the roles of autophagy-related protein 14 (ATG14) and miR199a-5p in the regulation of insulin sensitivity, we injected Ad-miR199a-5p with or without Ad-ATG14 viruses into WT C57BL/6J mice before performing functional assays. Moreover, we infected HepG2 cells or primary hepatocytes with Ad-anti-miR199a-5p or Ad-miR199a-5p viruses to determine the effect of miR199a-5p on insulin resistance in vitro. Finally, we explored the clinical relevance of miR199a-5p by examining the expression level of miR199a-5p in liver samples derived from diabetes patients. We first demonstrated that knocking down miR199a-5p led to decreased glucose tolerance and clearance in vivo, whereas the overexpression of miR199a-5p had the opposite effect. We further identified ATG14 as the target of miR199a-5p, and ATG14 partially rescued miR199a-5p-potentiated glucose and insulin tolerance. In addition, transmission electron microscopy data and western blot data regarding ATG14, LC3 and BECLIN1 illustrated that miR199a-5p regulates autophagy via ATG14. Knocking down miR199a-5p in primary hepatocytes and HepG2 cells suppressed the insulin-stimulated phosphorylation of insulin receptor β, glycogen synthase kinase 3β and protein kinase B, whereas the overexpression of miR199a-5p further potentiated their phosphorylation. Finally, we detected upregulated miR199a-5p levels, which were correlated with reduced ATG14 mRNA levels and downregulated autophagy in liver samples obtained from diabetes patients. Our study uncovered a novel biological role of miR199a-5p in the regulation of hepatic insulin sensitivity via ATG14-mediated autophagy.
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使用钙通道阻滞剂对肥胖引起的自噬停滞的药理校正。
影响因子：
16.6
作者：
Park, Hwan-Woo;Park, Haeli;Semple, Ian A.;Jang, Insook;Ro, Seung-Hyun;Kim, Myungjin;Cazares, Victor A.;Stuenkel, Edward L.;Kim, Jung-Jae;Kim, Jeong Sig;Lee, Jun Hee
通讯作者：
Lee, Jun Hee
影响因子：
--
作者：
Williams MD;Mitchell GM
通讯作者：
Mitchell GM
DOI：
10.1007/978-1-59745-019-5_13
发表时间：
2010-01-01
期刊：
MOUSE CELL CULTURE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Li, Wan-Chun;Ralphs, Kate L.;Tosh, David
通讯作者：
Tosh, David
MiR-199a-5p 与恶性肿瘤呈负相关，并通过靶向肝癌中的己糖激酶 2 来调节糖酵解和乳酸的产生
影响因子：
13.5
作者：
Guo, Weijie;Qiu, Zhaoping;He, Xianghuo
通讯作者：
He, Xianghuo
影响因子：
4.5
作者：
Lino Cardenas CL;Henaoui IS;Courcot E;Roderburg C;Cauffiez C;Aubert S;Copin MC;Wallaert B;Glowacki F;Dewaeles E;Milosevic J;Maurizio J;Tedrow J;Marcet B;Lo-Guidice JM;Kaminski N;Barbry P;Luedde T;Perrais M;Mari B;Pottier N
通讯作者：
Pottier N