Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response.
Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response.
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载脂蛋白E4介导与胰岛素抵抗相关的脑血管功能障碍和餐后反应。
DOI：
10.1177/0271678x17746186
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发表时间：
2019-05
期刊：
影响因子：
--
通讯作者：
Raber J
中科院分区：
文献类型：
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作者：
Johnson LA;Torres ER;Weber Boutros S;Patel E;Akinyeke T;Alkayed NJ;Raber J
代谢功能障碍通常是由高饱和脂肪和高糖饮食引起的，与认知功能受损以及患上与年龄相关的认知衰退(ACD)和阿尔茨海默病(AD)的风险增加有关。与载脂蛋白的E3亚型(ApoE)相比，E4亚型是ACD、AD以及在各种环境挑战(包括高脂肪饮食(HFD)等饮食挑战后出现认知障碍)的主要遗传风险因素。胰岛素抵抗(IR)和E4都与代谢和血管损伤有关。脑代谢和脑血管功能的缺陷被认为是导致这些损害的始动事件。在目前的研究中，我们使用了人类载脂蛋白E靶向替换小鼠和高脂蛋白诱导的肥胖的模型来研究E4和IR之间的潜在联系，包括安静时和餐后挑战。HFD诱导的IR与认知损害、脑血容量减少和葡萄糖摄取减少有关。这些影响在E4小鼠中比在E3小鼠中更深刻。此外，对外源性葡萄糖负荷的认知、代谢和脑血管反应显示出载脂蛋白E异构体依赖的反应，E4小鼠，而不是E3小鼠，显著受益于血糖飙升。
Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer’s disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose.