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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:841.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE^–/– Mice

Harry R. Davis, Jr; Lizbeth M. Hoos; Glen Tetzloff; Maureen Maguire; Li-ji Zhu; Michael P. Graziano; Scott W. Altmann

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.

Correspondence to Harry R. Davis Jr, Schering-Plough Research Institute, K15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033. 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.

Niemann-Pick C1 Like 1 (Npc1l1)/apoE null^–/– mice had a 77% reduction in cholesterol absorption. Fed chow or Western diets, plasma cholesterol was reduced, and atherosclerosis inhibited by >90% relative to apoE^–/– mice. Lack of Npc1l1, the target of ezetimibe, in apoE^–/– mice causes a nearly complete protection from atherogenesis.

Key Words: NPC1L1 • cholesterol absorption • atherosclerosis • ezetimibe • apoE^–/– mice

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