miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3
miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3
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DOI：
10.7150/thno.27425
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Peng, Jinyong
中科院分区：
文献类型：
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作者：
Xu, Lina;Li, Yue;Peng, Jinyong
糖脂代谢紊乱是2型糖尿病（T2DM）发生的重要原因。明确代谢紊乱的分子机制，探索药物靶点对T2DM的治疗至关重要。方法：检测miR-125a-5p在棕榈酸诱导的AML12细胞和2型糖尿病大鼠、小鼠肝脏中的表达水平，并验证其靶基因。通过功能获得和功能缺失的研究，在体内和体外进一步阐明了miR-125a-5p通过靶向STAT3调控糖脂代谢的作用。结果：我们发现，miR-125a-5p在糖尿病小鼠和大鼠肝脏中显著降低，STAT3被鉴定为miR-125a-5p的靶基因。在C57BL/6小鼠中过表达miR-125a-5p可降低STAT3水平，下调p-STAT3和SOCS3的表达水平。因此，srebp -1c介导的脂肪生成途径被抑制，PI3K/AKT途径被激活。此外，沉默miR-125a-5p可显著提高STAT3、p-STAT3和SOCS3的表达水平，从而激活SREBP-1c通路，抑制PI3K/AKT通路。因此，C57BL/6小鼠出现高血糖、高脂血症和肝糖原降低。在棕榈酸诱导的AML12细胞中，miR-125a-5p模拟物通过调节STAT3信号通路显著增加葡萄糖消耗和摄取，减少脂滴积累。与此一致的是，miR-125a-5p过表达明显抑制糖尿病小鼠KK-Ay中STAT3的表达，从而降低糖尿病小鼠的血糖和血脂水平，增加肝糖原含量，减少肝脂滴的积累。此外，在KK-Ay小鼠中抑制miR-125a-5p通过调节STAT3加重糖脂代谢功能障碍。结论：我们的研究结果证实miR-125a-5p可能是T2DM患者糖脂代谢的调节因子，通过靶向STAT3抑制肝脏脂肪生成和糖异生，提高糖原合成。
Glycolipid metabolic disorder is an important cause for the development of type 2 diabetes mellitus (T2DM). Clarification of the molecular mechanism of metabolic disorder and exploration of drug targets are crucial for the treatment of T2DM.Methods: We examined miR-125a-5p levels in palmitic acid-induced AML12 cells and the livers of type 2 diabetic rats and mice, and then validated its target gene. Through gain- and loss-of-function studies, the effects of miR-125a-5p via targeting of STAT3 on regulating glycolipid metabolism were further illustrated in vitro and in vivo.Results: We found that miR-125a-5p was significantly decreased in the livers of diabetic mice and rats, and STAT3 was identified as the target gene of miR-125a-5p. Overexpression of miR-125a-5p in C57BL/6 mice decreased STAT3 level and downregulated the expression levels of p-STAT3 and SOCS3. Consequently, SREBP-1c-mediated lipogenesis pathway was inhibited, and PI3K/AKT pathway was activated. Moreover, silencing of miR-125a-5p significantly increased the expression levels of STAT3, p-STAT3 and SOCS3, thus activating SREBP-1c pathway and suppressing PI3K/AKT pathway. Therefore, hyperglycemia, hyperlipidemia and decreased liver glycogen appeared in C57BL/6 mice. In palmitic acid-induced AML12 cells, miR-125a-5p mimic markedly increased glucose consumption and uptake and decreased the accumulation of lipid droplets by regulating STAT3 signaling pathway. Consistently, miR-125a-5p overexpression obviously inhibited STAT3 expression in diabetic KK-Ay mice, thereby decreasing blood glucose and lipid levels, increasing hepatic glycogen content, and decreasing accumulation of hepatic lipid droplets in diabetic mice. Furthermore, inhibition of miR-125a-5p in KK-Ay mice aggravated glycolipid metabolism dysfunction through regulating STAT3.Conclusions: Our results confirmed that miR-125a-5p should be considered as a regulator of glycolipid metabolism in T2DM, which can inhibit hepatic lipogenesis and gluconeogenesis and elevate glycogen synthesis by targeting STAT3.