Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption

Dietary Cholesterol consumption and intestinal Cholesterol absorption contribute to plasma Cholesterol levels, a risk factor for coronary heart disease. The molecular mechanism of sterol uptake from the lumen of the small intestine is poorly defined. We show that Niemann-Pick C1 Like 1(NPC1L1) protein plays a critical role in the absorption of intestinal Cholesterol. NPC1L1 expression is enriched in the small intestine and is in the brush border membrane of enterocytes. Although otherwise phenotypically normal, NPC1L1-deficient mice exhibit a substantial reduction in absorbed Cholesterol, which is unaffected by dietary supplementation of bile acids. Ezetimibe, a drug that inhibits Cholesterol absorption, had no effect in NPC1L1 knockout mice, suggesting that NPC1L1 resides in an ezetimibe-sensitive pathway responsible for intestinal Cholesterol absorption.