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 ( Npc111) prevents atherosclerosis in apoE null mice. Methods and Results - Npc111(-/-)/apoE null(-/-) mice were generated and found to have a significant reduction in cholesterol absorption (-77%) compared with wild-type or apoE(-/-) mice. Npc111/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(-/-), Npc111(-/-), wild-type, and ezetimibe-treated apoE(-/-) mice. Chylomicron remnant/VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet - fed Npc111/apoE(-/-) mice relative to apoE(-/-) mice. Male Npc111(-/-) and Npc111/ 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 Npc111/ apoE(-/-) mice relative to apoE(-/-) mice. Conclusions - Lack of Npc111, 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.