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首页> 外文期刊>Theranostics >miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3
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miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3

机译：miR-125a-5p通过靶向STAT3改善2型糖尿病的肝糖脂代谢紊乱

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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.
机译：糖脂代谢异常是2型糖尿病（T2DM）发生的重要原因。阐明代谢紊乱的分子机制和探索药物靶标对于T2DM的治疗至关重要。方法：我们检查了棕榈酸诱导的AML12细胞和2型糖尿病大鼠和小鼠肝脏中miR-125a-5p的水平，然后验证了其靶基因。通过功能获得和丧失的研究，在体内外进一步阐明了通过靶向STAT3调控miR-125a-5p对糖脂代谢的影响。结果：我们发现在糖尿病小鼠和大鼠的肝脏中，miR-125a-5p显着降低，STAT3被确定为miR-125a-5p的靶基因。在C57BL / 6小鼠中miR-125a-5p的过表达降低了STAT3水平，并下调了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显着增加STAT3，p-STAT3和SOCS3的表达水平，从而激活SREBP-1c途径并抑制PI3K / AKT途径。因此，C57BL / 6小鼠出现高血糖，高血脂和肝糖原减少。在棕榈酸诱导的AML12细胞中，miR-125a-5p模拟物通过调节STAT3信号通路显着增加了葡萄糖的消耗和摄取，并减少了脂滴的积累。一致地，miR-125a-5p的过表达明显抑制了糖尿病KK-Ay小鼠的STAT3表达，从而降低了血糖和脂质水平，增加了肝糖原含量，并减少了糖尿病小鼠中肝脂质滴的积累。此外，在KK-Ay小鼠体内对miR-125a-5p的抑制通过调节STAT3加剧了糖脂代谢功能障碍。结论：我们的结果证实，应将miR-125a-5p视为T2DM中糖脂代谢的调节剂，它可以通过靶向STAT3来抑制肝脂形成和糖异生，并提高糖原合成。

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