Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis
Department of Cardiovascular/Metabolic Disease and Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
09/2004; 279(32):33586-92. DOI: 10.1074/jbc.M405817200
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.
Available from: Yuwei Liu
- "Cholesterol absorption in the small intestine is a very complex process and requires several sterol transporters, enzymes and proteins. It starts with Niemann- Pick C1 like 1 protein (NPC1L1), which transports cholesterol from the lumen of intestine to enterocytes (Davis et al., 2004). "
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ABSTRACT: β-Sitosterol (SI) is hypocholesterolemic. The present study investigated whether the blockage of its hydroxyl group would abolish its cholesterol-lowering activity. The blockage was made by methylating and ethylating the hydroxyl group on C3 position, leading to formation of β-sitosteryl 3β-methoxy (SM) and β-sitosteryl 3β-ethoxy (SE) derivatives. Male hamsters were divided into five groups (n = 8 each) and fed the non-cholesterol diet (NCD), high cholesterol diet containing 5 mmol of cholesterol (HCD), or one of the three high cholesterol experimental diets with addition of 5 mmol of SI (HCD + SI), 5 mmol of SM (HCD + SM) and 5 mmol of SE (HCD + SE), respectively, for 8 weeks. Results showed that SI could significantly reduce plasma total cholesterol (TC) by 17% (P < 0.05), while SM and SE had no effect on plasma TC. It was concluded that the hydroxyl group was essential for SI to render its cholesterol-lowering activity and its blockage abolished this ability.
Available from: Rafaela Da Silva Marineli
- "It is possible that this route includes passive diffusion through the micelleforming proteins or by Niemann-Pick C1-like 1 (NPC1L1), which is an intestine protein that absorbs dietary and biliary cholesterol (Allayee et al. 2000; Weingärtner et al. 2011). Davis et al. (2004) showed that expression of NPC1L1 in mice increased the levels of plasma cholesterol, when compared to the results obtained for NPC1L1 null mice. The presence of this enteric protein seems to be important in the absorption of phytosterols, as well as cholesterol. "
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ABSTRACT: Phytosterols or plant sterols are important constituents of plant cells. These compounds exert very important biological effects, such as hypocholesterolemic and antioxidant activities. However, the mechanisms of action are yet poorly understood and until now, there is no data related to the effect of phytosterol consumption on the development of cardiovascular diseases. Through extensive literature review, the aim of this chapter is to present the main and most current scientific information on phytosterol biological effects in vivo, their metabolism, and their role in health.
Available from: Alexandra Schutkowski
- "Different factors could have caused the increased output of faecal cholesterol in the lupin protein group: (1) lupin protein isolate compared to casein could have affected the cholesterol absorption by modifying sterol transporter expression in the intestine, (2) lupin protein isolate could have un-specifically bound sterols in the gut lumen which in consequence increased cholesterol output, (3) lupin protein isolate could have contributed to an increased excretion of cholesterol via the bile, (4) lupin protein isolate could have influenced formation, solubility or composition of micelles which in turn affected cholesterol-uptake into the enterocytes or (5) lupin protein isolate could have affected the cholesterol efflux via modification of basolateral sterol transporter expression in the intestine. Several intestinal transporters are involved in trafficking cholesterol across the apical enterocyte membrane such as SR-BI , FAT/CD36 , NPC1L1  and ABC transporters . All of these transporters have been found to be regulated by transcription . "
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ABSTRACT: Lupin proteins exert hypocholesterolemic effects in man and animals, although the underlying mechanism remains uncertain. Herein we investigated whether lupin proteins compared to casein modulate sterol excretion and mRNA expression of intestinal sterol transporters by use of pigs as an animal model with similar lipid metabolism as humans, and cellular cholesterol-uptake by Caco-2 cells.
Two groups of pigs were fed cholesterol-containing diets with either 230 g/kg of lupin protein isolate from L. angustifolius or 230 g/kg casein, for 4 weeks. Faeces were collected quantitatively over a 5 d period for analysis of neutral sterols and bile acids by gas chromatographically methods. The mRNA abundances of intestinal lipid transporters were analysed by real-time RT-PCR. Cholesterol-uptake studies were performed with Caco-2 cells that were incubated with lupin conglutin gamma, phytate, ezetimibe or albumin in the presence of labelled [4-14C]-cholesterol.
Pigs fed the lupin protein isolate revealed lower cholesterol concentrations in total plasma, LDL and HDL than pigs fed casein (P < 0.05). Analysis of faeces revealed a higher output of cholesterol in pigs that were fed lupin protein isolate compared to pigs that received casein (+57.1%; P < 0.05). Relative mRNA concentrations of intestinal sterol transporters involved in cholesterol absorption (Niemann-Pick C1-like 1, scavenger receptor class B, type 1) were lower in pigs fed lupin protein isolate than in those who received casein (P < 0.05). In vitro data showed that phytate was capable of reducing the uptake of labelled [4-14C]-cholesterol into the Caco-2 cells to the same extend as ezetimibe when compared to control (-20.5% vs. -21.1%; P < 0.05).
Data reveal that the cholesterol-lowering effect of lupin protein isolate is attributable to an increased faecal output of cholesterol and a reduced intestinal uptake of cholesterol. The findings indicate phytate as a possible biofunctional ingredient of lupin protein isolate.
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