Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewNiemann–Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter
Introduction
Intestinal cholesterol absorption begins with the micellar solubilization of both dietary and biliary cholesterol in the lumen of the small intestine. In humans, approximately 50% of intestinal cholesterol is absorbed, in which about two thirds is derived from the bile and the other one third is derived from the diet. The free cholesterol (unesterified cholesterol) is then transferred from the micelles to the surface of the brush border membrane of intestinal enterocytes. Until recently, the mechanism by which free cholesterol moves from the intestinal lumen into the absorptive enterocytes lining the proximal small intestine has been poorly understood. The identification of ezetimibe as a potent selective inhibitor of intestinal cholesterol uptake and absorption in animals and humans revealed that the intestinal cholesterol uptake process is mediated by a specific transporter [1], [2], [3].
Section snippets
Identification of NPC1L1 as an intestinal sterol transporter
Based on the properties of the cholesterol absorption inhibitor ezetimibe in animal models of intestinal cholesterol uptake, it was predicted that a cholesterol transporter would be expressed in jejunal enterocytes, where cholesterol is absorbed, and localized to the brush border membrane [1], [2], [3]. Biochemical and molecular biological techniques were used for many years in an attempt to identify the intestinal transporter ezetimibe inhibited, but these studies were unsuccessful. Several
NPC1L1 and phytosterols
Ezetimibe has been shown to reduce plasma phytosterol levels in patients with hypercholesterolemia and in patients with sitosterolemia, which is caused by a mutation in either ABCG5 or ABCG8 [2], [10]. ABCG5 and ABCG8 are expressed on the apical surface of hepatocytes and enterocytes, and their function is required to export phytosterols into the bile and intestinal lumen, respectively (Fig. 1) [11], [12]. Phytosterols are poorly absorbed compared to cholesterol, and it was not known whether
Hepatic NPC1L1
In rodents (mice, hamsters, and rats) NPC1L1 is primarily only found in the small intestine, while in humans and other species (monkeys, pigs and dogs) NPC1L1 is also expressed in the liver, but its highest expression in these species is also in the small intestine [4], [14], [15], [16], [17]. In the liver NPC1L1 has been shown to be localized to the hepatocyte canalicular membrane [15]. Temel et al. [18] generated transgenic mice that expressed NPC1L1 in their livers. These mice were
NPC1L1 and atherosclerosis
It has been demonstrated that ezetimibe treatment inhibits cholesterol absorption, reduces plasma cholesterol and inhibits the development and progression of atherosclerosis in apoE (−/−) mice by > 90% when fed western or cholesterol-free diets [20]. Consequently, with the discovery of NPC1L1, studies were preformed to determine the effect that mice lacking Npc1l1 would have on the development and progression of atherosclerosis in apoE (−/−) mice. Npc1l1(−/−)/apoE null (−/−) mice were generated
NPC1L1 and other proposed intestinal sterol transporters
NPC1L1 is a sterol transporter localized in jejunal enterocytes and is critical for intestinal cholesterol and phytosterol uptake and absorption. Scavenger receptor class B, Type I (SR-B1) is also localized in jejunal enterocytes and has been proposed to play a role in cholesterol absorption and the activity of ezetimibe [22]. We determined if deficiency of SR-B1 and Npc1l1 in mice results in additional effects on cholesterol absorption and whole-body cholesterol homeostasis [23]. Cholesterol
NPC1L1 and gene regulation
Since cholesterol synthesis and cellular uptake is tightly regulated, blocking intestinal cholesterol uptake by NPC1L1 deficiency or inhibition may affect the intestinal and hepatic expression of genes involved in sterol metabolism. Intestinal and hepatic LDL-receptor, HMG CoA synthase, and other genes in the cholesterol synthetic pathway were increased in cholesterol-fed Npc1l1 null mice, in contrast to Npc1l1 (+/−) and (+/+) mice, where these genes were down regulated with cholesterol feeding
NPC1L1, ezetimibe binding, and cholesterol uptake
Whole animal studies have established that NPC1L1 is central to cholesterol and phytosterol uptake into enterocytes and is in a pathway sensitive to ezetimibe. The specific molecular role for NPC1L1 in the action of ezetimibe remained unclear until binding of labeled ezetimibe to human NPC1L1 expressing cells demonstrated a specific, single site, saturable binding profile [33]. Ezetimibe clearly showed cell surface membrane binding to the NPC1L1-expressing cells, which was completely abolished
NPC1L1 genetic variants and cholesterol absorption
Polymorphisms in the human NPC1L1 gene have been found to affect cholesterol homeostasis by influencing sterol absorption and plasma LDL cholesterol levels [1], [39]. Non-synonymous sequence variants in NPC1L1 were reported to be more common among individuals with low cholesterol absorption than high cholesterol absorption [39]. Forty five coding single nucleotide polymorphisms (SNPs) or non-synonymous sequence variants have been reported thus far for NPC1L1 (Fig. 2). S. Fahmi et al. [40] found
Conflict of Interest
All authors are employed at Schering-Plough Corporation.
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