Involvement of apolipoprotein E in excess fat accumulation and insulin resistance
Involvement of apolipoprotein E in excess fat accumulation and insulin resistance
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DOI：
10.2337/db06-0144
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发表时间：
2007-01-01
期刊：
影响因子：
7.7
通讯作者：
Oka, Yoshitomo
中科院分区：
文献类型：
--
作者：
Gao, Junhong;Katagiri, Hideki;Oka, Yoshitomo
虽然载脂蛋白E （apoE）在脂质代谢中起主要作用，但其在葡萄糖和能量稳态中的作用尚不清楚。在此，我们建立了apoE缺陷遗传性肥胖Ay (apoE(-/-)；Ay / +)老鼠。缺乏ApoE的小鼠可以防止肥胖的发生，减少肝脏和脂肪组织中的脂肪堆积。载脂蛋白e (- / -);Ay/+小鼠表现出比apoE（+/+）更好的葡萄糖耐量；Ay / +老鼠。胰岛素耐量试验和高胰岛素-正血糖钳夹研究显示，尽管血浆游离脂肪酸水平升高，但胰岛素敏感性有明显改善。这些代谢表型被腺病毒补充载脂蛋白e蛋白逆转，表明循环载脂蛋白e参与了肥胖和肥胖相关代谢紊乱的增加。缺乏apoE的VLDL进入肝脏和脂肪细胞的摄取被明显抑制，但脂肪细胞在apoE(-/-)；Ay/+小鼠表现出正常分化，表明apoe依赖性VLDL运输参与肥胖的发展，即多余脂肪的积累。有趣的是,载脂蛋白e (- / -);Ay/+小鼠表现出食物摄入量减少和能量消耗增加。配对饲养实验表明，这些现象都有助于与apoE缺乏相关的肥胖抗性表型。因此，apoE参与维持能量稳态。apoe依赖性脂肪堆积是代谢综合征的一个有希望的治疗靶点。
Although apolipoprotein E (apoE) is well known to play a major role in lipid metabolism, its role in glucose and energy homeostasis remains unclear. Herein, we established apoE-deficient genetically obese Ay (apoE(-/-);Ay/+) mice. ApoE deficiency in Ay mice prevented the development of obesity, with decreased fat accumulation in the liver and adipose tissues. ApoE(-/-);Ay/+ mice exhibited better glucose tolerance than apoE(+/+);Ay/+ mice. Insulin tolerance testing and hyperinsulinemic-euglycemic clamp study revealed marked improvement of insulin sensitivity, despite increased plasma free fatty acid levels. These metabolic phenotypes were reversed by adenoviral replenishment of apoE protein, indicating circulating apoE to be involved in increased adiposity and obesity-related metabolic disorders. Uptake of apoE-lacking VLDL into the liver and adipocytes was markedly inhibited, but adipocytes in apoE(-/-);Ay/+ mice exhibited normal differentiation, suggesting that apoE-dependent VLDL transport is involved in the development of obesity, i.e., surplus fat accumulation. Interestingly, apoE(-/-);Ay/+ mice exhibited decreased food intake and increased energy expenditure. Pair-feeding experiments indicate these phenomena to both contribute to the obesity-resistant phenotypes associated with apoE deficiency. Thus, apoE is involved in maintaining energy homeostasis. ApoE-dependent excess fat accumulation is a promising therapeutic target for the metabolic syndrome.