Affiliation:
1. From the Department of Cardiovascular/Metabolic Disease (H.R.D., L.M.H., G.T., L.-j.Z., M.P.G., S.W.A.) and the Department of Discovery Technologies (M.M.), Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ.
Abstract
Objective—
The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 (Npc1l1) prevents atherosclerosis in apoE null mice.
Methods and Results—
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.
Conclusions—
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
107 articles.
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