The structure and function of Niemann-Pick C1-like 1 protein

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 (NPC1 L1) is a polytopic transmembrane protein containing a sterol-sensing domain of unknown function. In 2004, NPC1 L1 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 NPC1 L1 function and proposes a model for NPC1 L1-dependent cholesterol uptake. Recent findings Cell culture experiments have shown that NPC1 L1 mediates cellular uptake of various sterols but seems to have lower affinity to plant sterols than cholesterol. Transgenic animal studies have demonstrated that hepatic NPC1 L1 has the potential to regulate biliary cholesterol excretion. Cholesterol and many transcriptional factors appear to regulate NPC1 L1 gene expression. NPC1 L1 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 NPC1 L1-dependent cholesterol uptake, which may reconcile disagreement regarding NPC1 L1 subcellular localization. Summary NPC1 L1 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.