Davis Harry R, Hoos Lizbeth M, Tetzloff Glen, Maguire Maureen, Zhu Li-ji, Graziano Michael P, Altmann Scott W
Department of Cardiovascular/Metabolic Disease, Schering-Plough Research Institute, K15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):841-9. doi: 10.1161/01.ATV.0000257627.40486.46. Epub 2007 Jan 11.
The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 (Npc1l1) prevents atherosclerosis in apoE null mice.
Npc1l1(-/-)/apoE null-/- mice were generated and found to have a significant reduction in cholesterol absorption (-77%) compared with wild-type or apoE-/- mice. Npc1l1/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-/-, Npc1l1-/-, wild-type, and ezetimibe-treated apoE-/- mice. Chylomicron remnant/VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet-fed Npc1l1/apoE-/- mice relative to apoE-/- mice. Male Npc1l1-/- and Npc1l1/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 Npc1l1/apoE-/- mice relative to apoE-/- mice.
Lack of Npc1l1, 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.
本研究旨在确定尼曼-匹克C1样蛋白1（Npc1l1）的缺乏是否能预防载脂蛋白E基因敲除小鼠的动脉粥样硬化。
构建了Npc1l1（-/-）/载脂蛋白E基因敲除（-/-）小鼠，发现与野生型或载脂蛋白E基因敲除小鼠相比，其胆固醇吸收显著降低（-77%）。给Npc1l1/载脂蛋白E基因敲除小鼠喂食普通饲料或西式饮食24周，然后将其脂蛋白、肝脏和胆汁中的胆固醇以及动脉粥样硬化的发展情况与载脂蛋白E基因敲除、Npc1l1基因敲除、野生型以及依泽替米贝治疗的载脂蛋白E基因敲除小鼠进行比较。相对于载脂蛋白E基因敲除小鼠，喂食普通饲料和西式饮食的Npc1l1/载脂蛋白E基因敲除小鼠的乳糜微粒残粒/极低密度脂蛋白胆固醇水平均降低了80%至90%。雄性Npc1l1基因敲除和Npc1l1/载脂蛋白E基因敲除小鼠对饮食诱导的高胆固醇血症完全有抵抗力，雄性和雌性小鼠对肝脏和胆汁胆固醇水平的升高也完全有抵抗力。相对于载脂蛋白E基因敲除小鼠，雄性和雌性Npc1l1/载脂蛋白E基因敲除小鼠的主动脉病变表面积的动脉粥样硬化减少了99%，无名动脉内膜病变面积减少了94%至97%，主动脉根部病变面积减少了>90%。
在载脂蛋白E基因敲除小鼠中，缺乏胆固醇吸收抑制剂依泽替米贝的分子靶点Npc1l1会导致胆固醇吸收和血浆胆固醇水平显著降低，并在胆固醇喂养和非胆固醇喂养条件下对动脉粥样硬化的发展产生几乎完全的保护作用。
