Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1.
Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1.
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DOI：
10.2337/db09-0047
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发表时间：
2009-10
期刊：
影响因子：
7.7
通讯作者：
Feldman EL
中科院分区：
文献类型：
--
作者：
Vincent AM;Hayes JM;McLean LL;Vivekanandan-Giri A;Pennathur S;Feldman EL
神经病变是糖尿病常见且严重的并发症。2型糖尿病患者多种代谢缺陷导致背根神经节（DRG）神经元氧化损伤。我们之前的工作重点是高血糖，清楚地表明线粒体氧化应激和DRG神经元的急性损伤的诱导；然而，这种机制并不是体内产生神经病变的唯一因素。血脂异常也与神经病变的发展相关，甚至在糖尿病前期患者中也是如此。本研究旨在探讨血脂异常在神经病变中的作用。小鼠（n = 10）被喂食对照（10% kcal %脂肪）或高脂肪（45% kcal %脂肪）饮食，以探索血浆脂质对神经病变发展的影响。我们还使用氧化ldl （oxldl）检测了培养的成年大鼠DRG神经元中氧化脂质介导的损伤。高脂肪饮食的老鼠会增加氧化低密度脂蛋白和全身和神经氧化应激。在糖耐量受损之前，他们会出现神经传导速度（NCV）和感觉缺陷。在体外，oxLDL通过与受体凝集素样oxLDL受体(LOX)-1和随后的NAD(P)H氧化酶活性相互作用导致严重的DRG神经元氧化应激。由低密度脂蛋白和高葡萄糖引起的氧化应激是附加性的。2型糖尿病的多种代谢缺陷通过不同的机制直接损伤DRG神经元，这些机制都导致氧化应激。血脂异常导致高水平的oxldl，可能通过LOX-1损伤DRG神经元，并促进糖尿病神经病变的发展。
Neuropathy is a frequent and severe complication of diabetes. Multiple metabolic defects in type 2 diabetic patients result in oxidative injury of dorsal root ganglia (DRG) neurons. Our previous work focused on hyperglycemia clearly demonstrates induction of mitochondrial oxidative stress and acute injury in DRG neurons; however, this mechanism is not the only factor that produces neuropathy in vivo. Dyslipidemia also correlates with the development of neuropathy, even in pre-diabetic patients. This study was designed to explore the contribution of dyslipidemia in neuropathy. Mice (n = 10) were fed a control (10% kcal %fat) or high-fat (45% kcal %fat) diet to explore the impact of plasma lipids on the development of neuropathy. We also examined oxidized lipid–mediated injury in cultured DRG neurons from adult rat using oxidized LDLs (oxLDLs). Mice on a high-fat diet have increased oxLDLs and systemic and nerve oxidative stress. They develop nerve conduction velocity (NCV) and sensory deficits prior to impaired glucose tolerance. In vitro, oxLDLs lead to severe DRG neuron oxidative stress via interaction with the receptor lectin-like oxLDL receptor (LOX)-1 and subsequent NAD(P)H oxidase activity. Oxidative stress resulting from oxLDLs and high glucose is additive. Multiple metabolic defects in type 2 diabetes directly injure DRG neurons through different mechanisms that all result in oxidative stress. Dyslipidemia leads to high levels of oxLDLs that may injure DRG neurons via LOX-1 and contribute to the development of diabetic neuropathy.