Deficiency of Niemann-Pick C1 like 1 prevents atherosclerosis in ApoE-/- mice
Deficiency of Niemann-Pick C1 like 1 prevents atherosclerosis in ApoE-/- mice
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DOI：
10.1161/01.atv.0000257627.40486.46
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发表时间：
2007-04-01
影响因子：
8.7
通讯作者：
Altmann, Scott W.
中科院分区：
文献类型：
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作者：
Davis, Harry R., Jr.;Hoos, Lizbeth M.;Altmann, Scott W.
目的 - 本研究的目的是确定 Niemann-Pick C1 Like 1 (Npc111) 的缺陷是否可以预防 apoE null 小鼠的动脉粥样硬化。方法和结果 - 生成 Npc111(-/-)/apoE null(-/-) 小鼠，发现与野生型或 apoE(-/-) 小鼠相比，其胆固醇吸收显着减少 (-77%)。 Npc111/apoE(-/-)小鼠采用食物或西方饮食喂养24周，然后将脂蛋白、肝脏和胆汁胆固醇以及动脉粥样硬化的发展与apoE(-/-)、Npc111(-/-)、野生型和依折麦布治疗的apoE(-/-)小鼠进行比较。相对于 apoE(-/-) 小鼠，在普通饮食和西方饮食喂养的 Npc111/apoE(-/-) 小鼠中，乳糜微粒残留/VLDL 胆固醇水平均降低了 80% 至 90%。雄性Npc111(-/-)和Npc111/apoE(-/-)小鼠完全抵抗饮食诱导的高胆固醇血症，雄性和雌性小鼠都完全抵抗肝脏和胆汁胆固醇水平的增加。与apoE(-/-)小鼠相比，雄性和雌性Npc111/apoE(-/-)小鼠的主动脉病变表面积的动脉粥样硬化减少了99%，无名动脉内膜病变区域的动脉粥样硬化减少了94%至97%，主动脉根部病变区域的动脉粥样硬化减少了>90%。 结论 - 缺乏胆固醇吸收抑制剂的分子靶点Npc111在apoE(-/-)小鼠中，依折麦布可显着降低胆固醇吸收和血浆胆固醇水平，并且在胆固醇喂养和非胆固醇喂养条件下几乎完全防止动脉粥样硬化的发展。
Objective - The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 ( Npc111) prevents atherosclerosis in apoE null mice.Methods and Results - Npc111(-/-)/apoE null(-/-) mice were generated and found to have a significant reduction in cholesterol absorption (-77%) compared with wild-type or apoE(-/-) mice. Npc111/apoE(-/-) mice were fed a chow or Western diet for 24 weeks, then lipoprotein, hepatic, and biliary cholesterol, and atherosclerosis development was compared with apoE(-/-), Npc111(-/-), wild-type, and ezetimibe-treated apoE(-/-) mice. Chylomicron remnant/VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet - fed Npc111/apoE(-/-) mice relative to apoE(-/-) mice. Male Npc111(-/-) and Npc111/ apoE(-/-) mice were completely resistant to diet induced hypercholesterolemia, and both male and female mice were completely resistant to increases in hepatic and biliary cholesterol levels. Atherosclerosis was reduced 99% in aortic lesion surface area, 94% to 97% in innominate artery intimal lesion area, and > 90% in aortic root lesion area in both male and female Npc111/ apoE(-/-) mice relative to apoE(-/-) mice.Conclusions - Lack of Npc111, the molecular target of the cholesterol absorption inhibitor ezetimibe, in apoE(-/-) mice results in a significant reduction in cholesterol absorption and plasma cholesterol levels, and causes a nearly complete protection from the development of atherosclerosis, under both cholesterol-fed and non - cholesterol-fed conditions.