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.