Apolipoprotein E2 accentuates postprandial inflammation and diet-induced obesity to promote hyperinsulinemia in mice.
Apolipoprotein E2 accentuates postprandial inflammation and diet-induced obesity to promote hyperinsulinemia in mice.
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作者：
Kuhel DG;Konaniah ES;Basford JE;McVey C;Goodin CT;Chatterjee TK;Weintraub NL;Hui DY
遗传学研究揭示了载脂蛋白 E (apoE) 基因的 ε2 等位基因与较高的代谢性疾病风险之间的关联。本研究比较了内源性小鼠基因已被人类 APOE2 或 APOE3 基因取代的 C57BL/6 小鼠（APOE2 和 APOE3 小鼠），以确定 ε2 与肥胖和糖尿病之间关系的潜在机制。与APOE3小鼠相比，APOE2小鼠的空腹血脂和胰岛素水平升高，并在喂食富含脂质的食物2小时后表现出长时间的餐后高脂血症，并伴有粒细胞数量增加和炎症。与APOE3小鼠相比，当维持西式高脂肪、高胆固醇饮食时，APOE2小鼠也表现出肥胖增加。在 APOE2 小鼠的脂肪组织中也观察到脂肪组织功能障碍，伴有巨噬细胞浸润增加、丰富的冠状结构和炎症。严重的脂肪细胞功能障碍和组织炎症与在喂食西式饮食后在 APOE2 小鼠中观察到的严重高胰岛素血症相对应。总而言之，这些数据表明，含有 apoE2、富含甘油三酯的脂蛋白的血浆清除率受损，会促进脂质重新分配到中性粒细胞和脂肪细胞，从而加剧炎症和肥胖，从而加速高胰岛素血症的发展，最终导致晚期代谢疾病。
Genetic studies have revealed the association between the ε2 allele of the apolipoprotein E (apoE) gene and greater risk of metabolic diseases. This study compared C57BL/6 mice in which the endogenous mouse gene has been replaced by the human APOE2 or APOE3 gene (APOE2 and APOE3 mice) to identify the mechanism underlying the relationship between ε2 and obesity and diabetes. In comparison with APOE3 mice, the APOE2 mice had elevated fasting plasma lipid and insulin levels and displayed prolonged postprandial hyperlipidemia accompanied by increased granulocyte number and inflammation 2 h after being fed a lipid-rich meal. In comparison with APOE3 mice, the APOE2 mice also showed increased adiposity when maintained on a Western-type, high-fat, high-cholesterol diet. Adipose tissue dysfunction with increased macrophage infiltration, abundant crown-like structures, and inflammation were also observed in adipose tissues of APOE2 mice. The severe adipocyte dysfunction and tissue inflammation corresponded with the robust hyperinsulinemia observed in APOE2 mice after being fed the Western-type diet. Taken together, these data showed that impaired plasma clearance of apoE2-containing, triglyceride-rich lipoproteins promotes lipid redistribution to neutrophils and adipocytes to accentuate inflammation and adiposity, thereby accelerating the development of hyperinsulinemia that will ultimately lead to advanced metabolic diseases.
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