Center for Regenerative Medicine, Institute for Translational Medicine, Qingdao University, Qingdao, 266021, China.
Center for Regenerative Medicine, Institute for Translational Medicine, Qingdao University, Qingdao, 266021, China; School of Basic Medical Sciences, Qingdao University, Qingdao, China.
Mol Cell Endocrinol. 2020 May 15;508:110793. doi: 10.1016/j.mce.2020.110793. Epub 2020 Mar 27.
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.
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).
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.
心血管并发症是糖尿病患者死亡和发病的主要原因。胰岛素敏感性降低是糖尿病心血管疾病发病机制的主要原因。基于我们之前的研究，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着重要作用。磷酸酶（LPP3）是合成 DAG 的关键酶，对于心脏的正常功能和血管健康是必不可少的。然而，脂肪组织中 LPP3 的敲低会增加胰岛素敏感性，这表明 LPP3 的调节在心脏中可能很复杂。本研究旨在探讨 LPP3 在糖尿病心脏胰岛素敏感性中的作用，并确定潜在的上游靶点与糖尿病心肌病相关。
小鼠喂食高脂肪饮食（HF）或低脂肪饮食（对照）长达 24 周。24 周后，我们发现与对照组相比，高脂肪饮食诱导的心脏功能障碍与 LPP3 的升高有关（P<0.05）。此外，LPP3 的敲低挽救了棕榈酸单独处理对心肌细胞葡萄糖摄取的损害（P<0.05）。此外，我们确定了 miR-184 作为靶向 LPP3 的上游调节剂，并进一步证实了 DAG 与胰岛素敏感性之间的联系。miR-184 模拟物转染挽救了棕榈酸单独处理对葡萄糖摄取和葡萄糖消耗的损害（P<0.05）。
在高脂肪饮食喂养的小鼠心脏中，增加的 LPP3 通过增加 DAG 水平导致胰岛素抵抗。一种小的非编码 RNA，miR-184，至少部分调节了这种信号通路，以减轻胰岛素抵抗。
