Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

Science ◽  
2004 ◽  
Vol 303 (5661) ◽  
pp. 1201-1204 ◽  
Author(s):  
S. W. Altmann
Keyword(s):  
Cholesterol Absorption ◽  
Intestinal Cholesterol Absorption ◽  
Niemann Pick

scholarly journals A role for NPC1 and NPC2 in intestinal cholesterol absorption – the hypothesis gutted

2007 ◽  
Vol 408 (1) ◽  
Author(s):  
Laura Liscum
Keyword(s):  
Endoplasmic Reticulum ◽  
Dietary Cholesterol ◽  
Cholesterol Absorption ◽  
Cholesterol Transport ◽  
Intestinal Epithelial ◽  
Intestinal Cholesterol Absorption ◽  
Biochemical Journal ◽  
Good Target ◽  
Type C ◽  
Niemann Pick

Dietary and biliary cholesterol are taken up by intestinal epithelial cells and transported to the endoplasmic reticulum. At the endoplasmic reticulum, cholesterol is esterified, packaged into chylomicrons and secreted into the lymph for delivery to the bloodstream. NPC1L1 (Niemann–Pick C1-like 1) is a protein on the enterocyte brush-border membrane that facilitates cholesterol absorption. Cholesterol's itinerary as it moves to the endoplasmic reticulum is unknown, as is the identity of any cellular proteins that facilitate the movement. Two proteins that play an important role in intracellular cholesterol transport and could potentially influence NPC1L1-mediated cholesterol uptake are NPC1 and NPC2 (Niemann–Pick type C disease proteins 1 and 2). In this issue of the Biochemical Journal, Dixit and colleagues show that the absence or presence of NPC1 and NPC2 has no effect on intestinal cholesterol absorption in the mouse. Thus neither protein fills the gap in our knowledge of intra-enterocyte cholesterol transport. Furthermore, the NPC1/NPC2 pathway would not be a good target for limiting the uptake of dietary cholesterol.

Development and Physiological Regulation of Intestinal Lipid Absorption. III. Intestinal transporters and cholesterol absorption

2008 ◽  
Vol 294 (4) ◽  
pp. G839-G843 ◽  
Author(s):  
David Y. Hui ◽  
Eric D. Labonté ◽  
Philip N. Howles
Keyword(s):  
Basolateral Membrane ◽  
Scavenger Receptor ◽  
Cholesterol Absorption ◽  
Lipid Absorption ◽  
Intestinal Lumen ◽  
Intestinal Cholesterol Absorption ◽  
Physiological Regulation ◽  
A Cell ◽  
Intestinal Transporters ◽  
Niemann Pick

Intestinal cholesterol absorption is modulated by transport proteins in enterocytes. Cholesterol uptake from intestinal lumen requires several proteins on apical brush-border membranes, including Niemann-Pick C1-like 1 (NPC1L1), scavenger receptor B-I, and CD36, whereas two ATP-binding cassette half transporters, ABCG5 and ABCG8, on apical membranes work together for cholesterol efflux back to the intestinal lumen to limit cholesterol absorption. NPC1L1 is essential for cholesterol absorption, but its function as a cell surface transporter or an intracellular cholesterol transport protein needs clarification. Another ATP transporter, ABCA1, is present in the basolateral membrane to mediate HDL secretion from enterocytes.

scholarly journals Pravastatin Modulate Niemann-Pick C1-Like 1 and ATP-Binding Cassette G5 and G8 to Influence Intestinal Cholesterol Absorption

2015 ◽  
Vol 18 (5) ◽  
pp. 765 ◽  
Author(s):  
Atsushi Kawase ◽  
Seiji Hata ◽  
Mai Takagi ◽  
Masahiro Iwaki
Keyword(s):  
Mrna Expression ◽  
Hepg2 Cells ◽  
Regulatory Element ◽  
Cholesterol Absorption ◽  
Atp Binding ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Intestinal Cholesterol Absorption ◽  
Niemann Pick ◽  
Atp Binding Cassette

Purpose. Niemann-Pick C1-like 1 (NPC1L1), ATP-binding cassette (ABC)G5, and ABCG8 mediate intestinal cholesterol absorption. It is unclear whether pravastatin (PR) or ezetimibe (EZ) affect expression of these transporters. We examined the effects of PR and EZ on NPC1L1, ABCG5, and ABCG8 expression in human hepatoma HepG2 cells and the murine small intestine. We also assessed expression of the transcription factors liver X receptor (LXR)a, LXRb and sterol regulatory element-binding protein. Methods. Transporter mRNA levels were determined in murine small intestines 6 and 24 h after oral PR and EZ administration by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). In PR- and EZ-treated HepG2 cells, transporter and transcription factor mRNA and protein levels were examined by RT-PCR and western blot, respectively. Results. Significant decreases in NPC1L1, ABCG5, and ABCG8 mRNA expression were observed in the duodenum, but not jejunum and ileum, of mice 24 h after treatment with PR, but not EZ. In HepG2 cells, PR but not EZ treatment for 24 h also significantly decreased NPC1L1 protein and ABCG5, and ABCG8 mRNA expression, while increasing LXRa  mRNA levels. Conclusion. PR but not EZ treatment reduced duodenal cholesterol transporter expression in mice. PR-induced increases in LXRa  mRNA levels may be involved in attenuation of NPC1L1 expression, subsequently decreasing intestinal cholesterol absorption. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Phytosterol-mediated inhibition of intestinal cholesterol absorption is independent of ATP-binding cassette transporter A1

2006 ◽  
Vol 95 (3) ◽  
pp. 618-622 ◽  
Author(s):  
Laura Calpe-Berdiel ◽  
Joan Carles Escolà-Gil ◽  
Francisco Blanco-Vaca
Keyword(s):  
Cholesterol Absorption ◽  
Atp Binding ◽  
Lipoprotein Profile ◽  
Intestinal Cholesterol Absorption ◽  
Atp Binding Cassette Transporter ◽  
Niemann Pick ◽  
Increased Activity ◽  
Deficient Mice ◽  
Gene Expression Levels ◽  
Atp Binding Cassette

An increased activity of ATP-binding cassette transporter (ABC) A1 has been proposed as a mechanism underlying the hypocholesterolaemic effect of phytosterols. In the present study, ABCA1-deficient mice (ABCA1−/− mice) were used to examine the involvement of the ABCA1 in the reduction of intestinal cholesterol absorption in response to a phytosterol-enriched diet. A decrease in intestinal cholesterol absorption of 39 and 35% was observed after phytosterol treatment in ABCA1+/+ mice and in ABCA1−/− mice, respectively. No statistically significant changes in plasma lipoprotein profile or in intestinal ABCG5, ABCG8 and Niemann-Pick C1-Like 1 gene expression levels were found when phytosterol-treated ABCA1−/− mice and untreated ABCA1−/− mice were compared. We conclude that phytosterol inhibition of cholesterol absorption in mice is independent of ABCA1

scholarly journals Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake

2021 ◽  
Vol 7 (29) ◽  
pp. eabg3188
Author(s):  
Miaoqing Hu ◽  
Fan Yang ◽  
Yawen Huang ◽  
Xin You ◽  
Desheng Liu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Cholesterol Level ◽  
Cholesterol Absorption ◽  
Bound State ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Uptake ◽  
Cryo Electron Microscopy ◽  
Niemann Pick ◽  
Structural Insights ◽  
Apo State

Niemann-Pick C1-like 1 (NPC1L1) protein plays a central role in the intestinal cholesterol absorption and is the target of a drug, ezetimibe, which inhibits NPC1L1 to reduce cholesterol absorption. Here, we present cryo–electron microscopy structures of human NPC1L1 in apo state, cholesterol-enriched state, and ezetimibe-bound state to reveal molecular details of NPC1L1-mediated cholesterol uptake and ezetimibe inhibition. Comparison of these structures reveals that the sterol-sensing domain (SSD) could respond to the cholesterol level alteration by binding different number of cholesterol molecules. Upon increasing cholesterol level, SSD binds more cholesterol molecules, which, in turn, triggers the formation of a stable structural cluster in SSD, while binding of ezetimibe causes the deformation of the SSD and destroys the structural cluster, leading to the inhibition of NPC1L1 function. These results provide insights into mechanisms of NPC1L1 function and ezetimibe action and are of great significance for the development of new cholesterol absorption inhibitors.

scholarly journals Lactobacillus acidophilus ATCC 4356 Prevents Atherosclerosis via Inhibition of Intestinal Cholesterol Absorption in Apolipoprotein E-Knockout Mice

2014 ◽  
Vol 80 (24) ◽  
pp. 7496-7504 ◽  
Author(s):  
Ying Huang ◽  
Jinfeng Wang ◽  
Guihua Quan ◽  
Xiaojun Wang ◽  
Longfei Yang ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Lactobacillus Acidophilus ◽  
Plasma Cholesterol ◽  
Cholesterol Absorption ◽  
Peroxisome Proliferator ◽  
Intestinal Cholesterol Absorption ◽  
Peroxisome Proliferator Activated Receptor ◽  
Content Type ◽  
Apolipoprotein E Knockout Mice ◽  
Niemann Pick

ABSTRACTThe objective of this study was to investigate the effect ofLactobacillus acidophilusATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. Eight-week-old ApoE−/−mice were fed a Western diet with or withoutL. acidophilusATCC 4356 daily for 16 weeks.L. acidophilusATCC 4356 protected ApoE−/−mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P< 0.05) higher in theL. acidophilusATCC 4356 treatment groups than in the control groups. Furthermore,L. acidophilusATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration ofL. acidophilusATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore,L. acidophilusATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis.

scholarly journals Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption?

2007 ◽  
Vol 408 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Sayali S. Dixit ◽  
David E. Sleat ◽  
Ann M. Stock ◽  
Peter Lobel
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Absorption ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Uptake ◽  
Uptake Pathway ◽  
Molecular Events ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

NPC1L1 (Niemann–Pick C1-like 1), the pharmacological target of the cholesterol-uptake inhibitor ezetimibe, is a transporter localized on the brush border of enterocytes. Although this protein plays a key role in intestinal uptake of sterols, multiple molecular events that underlie intestinal cholesterol absorption have not been fully characterized. Two proteins that might be involved in this process are NPC1 and NPC2 (Niemann–Pick disease type C proteins 1 and 2), which function in the endosomal/lysosomal cholesterol egress pathway and whose deficiency results in NPC (Niemann–Pick type C) disease. The involvement of these proteins in intestinal cholesterol absorption was examined in mutant mice lacking either NPC1 or NPC2. Our data indicate that deficiencies in either protein do not have an effect on cholesterol uptake or absorption. This contrasts with recent results obtained for the fruitfly Drosophila melanogaster, which indicate that a deficiency of NPC1 (dNPC1a being its Drosophila homologue) leads to activation of an NPC1L1 (Drosophila homologue dNPC1b)-independent cholesterol uptake pathway, underscoring fundamental differences in mammalian and non-mammalian cholesterol metabolism.

Genetic background of cholesterol absorption efficacy. The role of Niemann–Pick C1-like 1 receptor and its genetic variation in lipid metabolism

2010 ◽  
Vol 151 (34) ◽  
pp. 1376-1383 ◽  
Author(s):  
Mariann Harangi ◽  
István Balogh ◽  
János Harangi ◽  
György Paragh
Keyword(s):  
Genetic Variation ◽  
Lipid Metabolism ◽  
Genetic Background ◽  
Cholesterol Absorption ◽  
Niemann Pick

A Niemann–Pick C1-like-1 egy szterolfelismerő domént tartalmazó membránfehérje, amelyet nagy számban expresszálnak csúcsi felszínükön a bélhámsejtek. Az utóbbi évek vizsgálatai azt igazolták, hogy ez a fehérje szükséges a szabad koleszterin bejutásához a bélhámsejtekbe a bél lumenéből. Biokémiai vizsgálatok azt igazolták, hogy a Niemann–Pick C1-like-1-hez kötődik az ezetimib, amely egy hatékony koleszterinfelszívódást gátló szer. A bélből történő koleszterinfelszívódás ütemében és az ezetimibkezelés hatékonyságában tapasztalt egyéni eltérések hátterében felmerült néhány Niemann–Pick C1-like-1 génvariáció oki szerepe.

Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors

2008 ◽  
Vol 295 (5) ◽  
pp. G873-G885 ◽  
Author(s):  
Z. Ravid ◽  
M. Bendayan ◽  
E. Delvin ◽  
A. T. Sane ◽  
M. Elchebly ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Expression ◽  
High Glucose ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Cholesterol Transport ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Uptake ◽  
Glucose Levels

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [14C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose ( P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of intestinal cholesterol transport. The high concentration of glucose enhanced the protein expression of the critical cholesterol transporter NPC1L1 and that of CD36 ( P < 0.02) and concomitantly decreased SR-BI protein mass ( P < 0.02). No significant changes were observed in the protein expression of ABCA1 and ABCG8, which act as efflux pumps favoring cholesterol export out of absorptive cells. At the same time, 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was decreased ( P < 0.007), whereas ACAT activity remained unchanged. Finally, increases were noted in the transcription factors LXR-α, LXR-β, PPAR-β, and PPAR-γ along with a drop in the protein expression of SREBP-2. Collectively, our data indicate that glucose at high concentrations may regulate intestinal cholesterol transport and metabolism in Caco-2/15 cells, thus suggesting a potential influence on the cholesterol absorption process in Type 2 diabetes.

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