The structure and function of Niemann–Pick C1-like 1 proteinYu, LiqingCurrent Opinion in Lipidology: June 2008 - Volume 19 - Issue 3 - p 263–269 doi: 10.1097/MOL.0b013e3282f9b563 Lipid metabolism: Edited by Jeffrey S. Cohn Buy Abstract Author InformationAuthors Article MetricsMetrics Purpose of review Intestinal absorption and biliary excretion of cholesterol represent two major pathways by which the body regulates cholesterol homeostasis. Niemann–Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein containing a sterol-sensing domain of unknown function. In 2004, NPC1L1 was identified to be essential for intestinal cholesterol absorption, a process that is sensitive to a cholesterol absorption inhibitor ezetimibe. This review summarizes recent studies on NPC1L1 function and proposes a model for NPC1L1-dependent cholesterol uptake. Recent findings Cell culture experiments have shown that NPC1L1 mediates cellular uptake of various sterols but seems to have lower affinity to plant sterols than cholesterol. Transgenic animal studies have demonstrated that hepatic NPC1L1 has the potential to regulate biliary cholesterol excretion. Cholesterol and many transcriptional factors appear to regulate NPC1L1 gene expression. NPC1L1 protein is enriched in the apical membrane of polarized cells and its intracellular itineraries are clearly regulated by cholesterol availability. Evidence suggests cholesterol-regulated clathrin-mediated endocytosis is likely the cellular basis for NPC1L1-dependent cholesterol uptake, which may reconcile disagreement regarding NPC1L1 subcellular localization. Summary NPC1L1 may have evolved at two sites (apical membrane of enterocytes and canalicular membrane of hepatocytes) to mediate cholesterol uptake through a clathrin-mediated endocytic process, protecting the body against fecal and biliary loss of cholesterol. Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA Correspondence to Liqing Yu, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA Tel: +1 336 716 0920; fax: +1 336 716 6279; e-mail: firstname.lastname@example.org © 2008 Lippincott Williams & Wilkins, Inc.