LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes.
LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes.
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DOI：
10.1007/s00125-015-3827-x
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发表时间：
2016-03
期刊：
影响因子：
8.2
通讯作者：
de Boer RA
中科院分区：
文献类型：
--
作者：
Cannon MV;Silljé HH;Sijbesma JW;Khan MA;Steffensen KR;van Gilst WH;de Boer RA
糖尿病性心肌病是一种由胰岛素信号传导受损、脂肪酸摄取增加和葡萄糖利用减少引发的心肌疾病。肝脏X受体（LXRs）是代谢稳态的关键转录调节因子。然而，它们在糖尿病心脏中的作用在很大程度上是未知的。我们将鼠Lxrα（也称为Nr 1h 3）克隆到α-肌球蛋白重链（αMhc;也称为Myh 6）启动子后面，以创建转基因（Lxrα-Tg）小鼠和转基因阴性同窝仔（野生型[WT]）。2型糖尿病的小鼠模型由高脂肪饮食（HFD，60%能量来自脂肪）诱导超过16周，并与低脂饮食（10%能量来自脂肪）进行比较。1型糖尿病的小鼠模型通过链脲佐菌素注射诱导超过12周。在Lxrα-Tg和WT小鼠中，HFD表现出相当的体重、血浆三酰甘油和胰岛素抵抗/OGTT增加。HFD使WT心脏的左心室重量显著增加21%，但Lxrα-Tg仅增加5%。为了阐明心脏中的代谢效应，microPET（正电子发射断层扫描）成像显示，在HFD的WT小鼠中，心脏葡萄糖摄取增加了1.4倍，但在Lxrα-Tg心脏中进一步增加了1.7倍，部分原因是5′腺苷一磷酸活化蛋白激酶（AMPK）磷酸化和葡萄糖转运蛋白4（GLUT 4）的恢复。相比之下，链脲佐菌素诱导的胰岛素信号传导消融降低了心脏葡萄糖摄取水平并导致心功能障碍，表明胰岛素可能在LXRα介导的葡萄糖摄取中起重要作用。染色质免疫沉淀试验确定利钠肽、心房利钠肽（ANP）和B型利钠肽（BNP）是心脏LXRα过表达的潜在直接靶点。心脏特异性LXRα过表达可改善HFD诱导的左心室肥厚进展，与糖尿病心肌病早期葡萄糖依赖和利钠肽信号传导增加相关。这些发现暗示了LXR在靶向糖尿病基础代谢紊乱方面的潜在保护作用。本文的在线版本（doi：10.1007/s 00125 -015-3827-x）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Diabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown. We cloned murine Lxrα (also known as Nr1h3) behind the α-myosin heavy chain (αMhc; also known as Myh6) promoter to create transgenic (Lxrα-Tg) mice and transgene-negative littermates (wild-type [WT]). A mouse model of type 2 diabetes was induced by a high-fat diet (HFD, 60% energy from fat) over 16 weeks and compared with a low-fat diet (10% energy from fat). A mouse model of type 1 diabetes was induced via streptozotocin injection over 12 weeks. HFD manifested comparable increases in body weight, plasma triacylglycerol and insulin resistance per OGTT in Lxrα-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxrα-Tg. To elucidate metabolic effects in the heart, microPET (positron emission tomography) imaging revealed that cardiac glucose uptake was increased by 1.4-fold in WT mice on an HFD, but further augmented by 1.7-fold in Lxrα-Tg hearts, in part through 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and restoration of glucose transporter 4 (GLUT4). By contrast, streptozotocin-induced ablation of insulin signalling diminished cardiac glucose uptake levels and caused cardiac dysfunction, indicating that insulin may be important in LXRα-mediated glucose uptake. Chromatin immunoprecipitation assays identified natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as potential direct targets of cardiac LXRα overexpression. Cardiac-specific LXRα overexpression ameliorates the progression of HFD-induced left ventricular hypertrophy in association with increased glucose reliance and natriuretic peptide signalling during the early phase of diabetic cardiomyopathy. These findings implicate a potential protective role for LXR in targeting metabolic disturbances underlying diabetes. The online version of this article (doi:10.1007/s00125-015-3827-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.