Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE-/- mice.
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.


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.
Davis
Harry R
HR
Department of Cardiovascular/Metabolic Disease, Schering-Plough Research Institute, K15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. harry.davis@spcorp.com
Hoos
Lizbeth M
LM
Tetzloff
Glen
G
Maguire
Maureen
M
Zhu
Li-ji
LJ
Graziano
Michael P
MP
Altmann
Scott W
SW
D000042:Absorption; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001646:Bile / Q000378:metabolism; D016122:Brachiocephalic Trunk / Q000473:pathology; D002784:Cholesterol / Q000097:blood / Q000493:pharmacokinetics; D018450:Disease Progression; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D001057:Apolipoproteins E; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D002784:Cholesterol