on January 11, 2007
Published online before print January 11, 2007, doi: 10.1161/01.ATV.0000257627.40486.46
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Submitted on October 25, 2006
Accepted on December 20, 2006
Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE-/- Mice
Harry R. Davis Jr *;
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.
* To whom correspondence should be addressed. E-mail: harry.davis{at}spcorp.com.
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.
Key words: NPC1L1 • cholesterol absorption • atherosclerosis • ezetimibe • apoE-/- mice
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