Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

TLDR

Intestinal cholesterol absorption, a key contributor to plasma cholesterol and coronary heart disease risk, is mediated by poorly understood mechanisms, with NPC1L1 highly expressed in the brush border of enterocytes. Loss of NPC1L1 markedly reduces intestinal cholesterol absorption and abolishes ezetimibe sensitivity, confirming NPC1L1 as essential for the ezetimibe‑responsive cholesterol uptake pathway.

Abstract

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.