MicroRNA-184 alleviates insulin resistance in cardiac myocytes and high fat diet-induced cardiac dysfunction in mice through the LPP3/DAG pathway
MicroRNA-184 alleviates insulin resistance in cardiac myocytes and high fat diet-induced cardiac dysfunction in mice through the LPP3/DAG pathway
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DOI：
10.1016/j.mce.2020.110793
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发表时间：
2020-05-15
影响因子：
4.1
通讯作者：
Wang, Jianxun
中科院分区：
文献类型：
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作者：
Chang, Wenguang;Fa, Hongge;Wang, Jianxun
目的：心血管并发症是糖尿病患者死亡和发病的主要原因。胰岛素敏感性丧失是糖尿病心血管疾病发病的一个重要因素。根据我们之前的研究，二酰基甘油（DAG）水平在高饱和脂肪酸诱导的胰岛素抵抗中起重要作用。磷脂酸磷酸酶（Phosphatidic acid phosphatase, LPP3）是合成DAG的关键酶，对心脏功能和血管健康至关重要。然而，脂肪敲低LPP3会增加胰岛素敏感性，这表明LPP3在心脏中的调节可能很复杂。本研究的目的是研究LPP3在糖尿病心脏胰岛素敏感性中的作用，并确定与糖尿病心肌病相关的潜在上游靶点。方法与结果：小鼠分别饲喂高脂饮食（HF）和低脂饮食（对照组），为期24周。24周后，我们发现与对照组相比，高脂饮食引起的心功能障碍与LPP3升高有关（P < 0.05）。此外，LPP3敲低可恢复棕榈酸盐单独治疗后的心肌细胞葡萄糖摄取（P < 0.05）。此外，我们发现miR-184是针对LPP3的上游调节因子，并进一步证实了DAG与胰岛素敏感性之间的联系。MiR-184模拟转染恢复了单独使用棕榈酸盐处理后受损的葡萄糖摄取和葡萄糖消耗（P < 0.05）。结论：在高脂饮食小鼠的心脏中，LPP3的增加通过增加DAG水平来促进胰岛素抵抗。一种小的非编码RNA miR-184至少部分调节这一信号通路以减轻胰岛素抵抗。
Aim: Cardiovascular complication is a major cause of mortality and morbidity in patients with diabetes. Insulin sensitivity loss is a major contributor to the pathogenesis of cardiovascular diseases in diabetes. Based on our previous research, diacylglycerol (DAG) levels play an important role in high saturated fatty acid-induced insulin resistance. Phosphatidic acid phosphatase (LPP3), a key enzyme for synthesizing DAG, is indispensable for normal cardiac functions and vascular health. However, adipose knockdown of LPP3 increases insulin sensitivity, suggesting that LPP3 regulation may be complicated in hearts. The aim of this study was to investigate LPP3 roles in diabetic cardiac insulin sensitivity and to identify potential upstream targets implicated in diabetic cardiomyopathy.Methods and results: Mice were fed a high fat diet (HF) or a low fat diet (control) for up to 24 weeks. After 24 weeks, we found that high fat diet-induced cardiac dysfunction is linked to elevated LPP3 compared to the control group (P < 0.05). In addition, knockdown of LPP3 rescued the glucose uptake that was impaired by palmitate treatment alone in cardiomyoblasts (P < 0.05). Furthermore, we identified miR-184 as an upstream regulator targeting LPP3 and further confirmed the link between DAG and insulin sensitivity. MiR-184 mimic transfection rescued the glucose uptake and glucose consumption that had been impaired by palmitate treatment alone (P < 0.05).Conclusion: In hearts of high fat diet-fed mice, increased LPP3 contributes to insulin resistance via increased DAG levels. A small non-coding RNA, miR-184, at least partially regulates this signal pathway to alleviate insulin resistance.