Phenotypic and Genetic Evidence for a More Prominent Role of Blood Glucose than Cholesterol in Atherosclerosis of Hyperlipidemic Mice.
Phenotypic and Genetic Evidence for a More Prominent Role of Blood Glucose than Cholesterol in Atherosclerosis of Hyperlipidemic Mice.
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高血脂和2型糖尿病（T2D）是动脉粥样硬化的主要危险因素。Apoe缺陷（Apoe−/−）小鼠在饲喂西方饮食后会出现高脂血症、动脉粥样硬化和T2D。在这里，我们试图剖析当血管系统暴露于高水平的胆固醇和葡萄糖时，血脂和葡萄糖与动脉粥样硬化斑块形成的表型和遗传关系。以LP/J和BALB/cJ Apoe - / -小鼠为原料，制备雄性F2小鼠，饲喂西方饲料12周。3号和15号染色体上的三个重要QTL Ath51、Ath52和Ath53被定位为动脉粥样硬化病变。近端Chr15上的Ath52与血浆葡萄糖、非高密度脂蛋白胆固醇和甘油三酯的QTL重叠。动脉粥样硬化病变大小与空腹、非空腹血糖、非空腹甘油三酯和体重有显著相关性，但与高密度脂蛋白、非高密度脂蛋白胆固醇和空腹甘油三酯水平无相关性。在调整空腹、非空腹血糖和非空腹甘油三酯后，动脉粥样硬化的Ath52从显著水平降至提示水平，但受HDL、非HDL胆固醇和空腹甘油三酯的影响最小。体重调整抑制了Ath52，但提高了远端Chr15的Ath53。这些结果证明了血糖和甘油三酯与动脉粥样硬化的表型和遗传联系，并表明血糖在高脂血症小鼠动脉粥样硬化斑块形成中的作用比胆固醇更突出。
Hyperlipidemia and type 2 diabetes (T2D) are major risk factors for atherosclerosis. Apoe-deficient (Apoe−/−) mice on certain genetic backgrounds develop hyperlipidemia, atherosclerosis, and T2D when fed a Western diet. Here, we sought to dissect phenotypic and genetic relationships of blood lipids and glucose with atherosclerotic plaque formation when the vasculature is exposed to high levels of cholesterol and glucose. Male F2 mice were generated from LP/J and BALB/cJ Apoe−/− mice and fed a Western diet for 12 weeks. Three significant QTL Ath51, Ath52 and Ath53 on chromosomes (Chr) 3 and 15 were mapped for atherosclerotic lesions. Ath52 on proximal Chr15 overlapped with QTL for plasma glucose, non-HDL cholesterol, and triglyceride. Atherosclerotic lesion sizes showed significant correlations with fasting, non-fasting glucose, non-fasting triglyceride, and body weight but no correlation with HDL, non-HDL cholesterol, and fasting triglyceride levels. Ath52 for atherosclerosis was down-graded from significant to suggestive level after adjustment for fasting, non-fasting glucose, and non-fasting triglyceride but minimally affected by HDL, non-HDL cholesterol, and fasting triglyceride. Adjustment for body weight suppressed Ath52 but elevated Ath53 on distal Chr15. These results demonstrate phenotypic and genetic connections of blood glucose and triglyceride with atherosclerosis, and suggest a more prominent role for blood glucose than cholesterol in atherosclerotic plaque formation of hyperlipidemic mice.
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