Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis

Abstract

Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.Cholesterol absorption of both dietary cholesterol and cholesterol cleared from the liver through biliary secretion contributes along with regulation of cholesterol biosynthesis to maintain a tight control of cholesterol homeostasis. The mechanism by which cholesterol moves from the intestinal lumen into the absorptive enterocytes lining the proximal small intestine is poorly understood. The identification of ezetimibe as a potent selective inhibitor of intestinal cholesterol uptake and absorption confirmed this mechanism as a key point of therapeutic intervention for lowering plasma cholesterol levels and indicated that this process is mediated by a specific transporter (1-4). Based on the properties of ezetimibe in animal models of cholesterol uptake, it was predicted that such a transporter would be expressed in jejunal enterocytes and localized to the brush border membrane, which forms the interface between the intestinal lumen and the intracellular compartments responsible for cholesterol esterification and packaging into chylomicrons.Through studies designed to understand the mechanism by which ezetimibe inhibits cholesterol absorption, we recently identified Niemann-Pick C1 Like 1 (NPC1L1) 1 as a critical protein for the intestinal absorption of dietary and biliary cholesterol (5). NPC1L1 was identified through a genomics-bioinformatics approach by sequencing an expression sequence tags library from rat jejunum, annotating the sequences, and searching databases for intestinal proteins with features of a cholesterol transporter (5). NPC1L1 was found to be highly expressed in the jejunum and localized on the surface of the absorptive enterocytes. Mice deficient in NPC1L1 exhibited a significant reduction in chol...

Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann–Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein

“…In the present study there was a close correlation between ABCG5 and ABCG8 mRNA in both diabetic and control subjects (Fig. 3), which was expected since these proteins are known to work in tandem to expel cholesterol from the enterocyte [18]. Diabetic patients had significantly lower ABCG5 and ABCG8 mRNA expression, suggesting they have an impairment in the re-excretion of cholesterol from the enterocyte back into the lumen.…”

“…We had expected that inhibition of cholesterol synthesis would increase NPC1L1 mRNA, since NPC1L1 deficiency results in upregulation of HMGCoA reductase. It has recently been shown that NPC1L1 null mice had increased HMGCoA synthase expression [18]. In acute experiments, inhibition of NPC1L1 by ezetimibe does not affect acute intestinal or hepatic cholesterol synthesis in rats [34], but we are unaware of any other studies on the relationship between HMGCoA reductase inhibition and NPC1L1 mRNA.…”

“…This is supported by the negative correlation between both postprandial chylomicron cholesterol and Apo B48, and ABCG5 and ABCG8 mRNA. NPC1L1 is responsible for transporting cholesterol across the membrane [18]. It is uncertain whether the protein also regulates the absorption of cholesterol synthesised in the intestine.…”

“…Ezetimibe was found to work by inhibiting NPC1L1 [17]. Thus this protein appears to play an important role in regulating intestinal cholesterol absorption [18]. The HMGCoA reductase inhibitors (statins) lower cholesterol and triglycerides.…”

Hypocholesterolaemic effects of plant sterol analogues are independent of ABCG5 and ABCG8 transporter expressions in hamsters

“…The present study did not show a significant effect of cholesterol on these two genes in the small intestine in hamsters. Some studies in mice have shown that dietary supplementation of cholesterol increases the expression of ABCG5 and ABCG8 in the small intestine 18,32,33,35 while others did not show any effect 25,36 . Studies in hamsters 23 and rats 34 did not show any effect of dietary cholesterol on ABCG5 and ABCG8 expressions in the small intestine.…”