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.

Abstract 378: Cholecystokinin Upregulates Cholesterol Absorption in Human Intestinal Epithelial Cells

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhongmao Guo ◽  
Ningya Zhang ◽  
Lemuel Dent ◽  
Emmanuel U Okoro ◽  
Hong Yang
Keyword(s):  
Cell Culture ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Plasma Cholesterol ◽  
Cholesterol Absorption ◽  
Adherent Cell ◽  
Cholesterol Transport ◽  
Suspension Cell Culture ◽  
Intestinal Epithelial ◽  
Intestinal Cholesterol Absorption

Excessive absorption of intestinal cholesterol is a risk factor for atherosclerosis. We previously reported that cholecystokinin (CCK) increases intestinal cholesterol absorption and plasma cholesterol level in mouse models. The goal of this study was to investigate the effect of CCK on cholesterol absorption and Niemann-Pick C1 Like 1 (NPC1L1) expression in human primary intestinal epithelial cells (HPIECs). Normal HPIECs were isolated from small bowl resection specimens, and purchased from the Lonza Group (Walkersville, MD) . Cholesterol absorption was determined by measuring transcellular cholesterol transport in adherent cell culture and cholesterol association and release in suspension cell culture. Surface NPC1L1 was isolated using a biotinylation kit and detected by western blotting. Our data demonstrate that HPIECs express both CCK receptor-1 and -2 (CCK1R; CCK2R). Treatment of HPIECs with 3 nM [Thr28, Nle31]-CCK for 60 min increased transcellular cholesterol transport, cholesterol association and release by ~38, 32 and 44%. Selective inhibition of CCK1R and CCK2R with antagonists (1 μM lorglumide or L365260) or selective knockdown of CCK1R and CCK2R with siRNAs attenuated CCK-induced cholesterol absorption. In the cells cultured on transwell membranes, CCK increased the level of NPC1L1 in the apical membrane by ~35% but did not alter the total NPC1L1 protein expression. Inhibition or knockdown of NPC1L1 attenuated CCK-induced cholesterol absorption. These data imply that activation of CCK1R/2R enhances cholesterol absorption by induction of NPC1L membrane translocation. [This study was supported by NIH grants U54MD0007593, UL1TR000445, and SC1HL101431]

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.

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.

scholarly journals Use of NBD-cholesterol to identify a minor but NPC1L1-independent cholesterol absorption pathway in mouse intestine

2011 ◽  
Vol 300 (1) ◽  
pp. G164-G169 ◽  
Author(s):  
Michelle R. Adams ◽  
Eddy Konaniah ◽  
James G. Cash ◽  
David Y. Hui
Keyword(s):  
Intestinal Mucosa ◽  
Cholesterol Absorption ◽  
Intestinal Lumen ◽  
Cholesterol Transport ◽  
Cholesteryl Esters ◽  
Main Function ◽  
Absorption Mechanism ◽  
Ezetimibe Treatment ◽  
Niemann Pick ◽  
A Minor

The importance of Niemann-Pick C1 Like-1 (NPC1L1) protein in intestinal absorption of dietary sterols, including both cholesterol and phytosterols, is well documented. However, the exact mechanism by which NPC1L1 facilitates cholesterol transport remains controversial. This study administered 22-( N(-7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol) and [3H]cholesterol to Npc1l1+/+ and Npc1l1−/− mice to determine whether NPC1L1 facilitates dietary sterol uptake by enterocytes and/or participates in intracellular sterol delivery to the endoplasmic reticulum (ER) for lipoprotein assembly before secretion into plasma circulation. Results showed that [3H]cholesterol absorption was reduced but not abolished in Npc1l1−/− mice compared with Npc1l1+/+ mice. In the presence of Pluronic L-81 to block pre-chylomicron exit from the ER, significant amounts of [3H]cholesterol were found to be associated with lipid droplets in the intestinal mucosa of both Npc1l1+/+ and Npc1l1−/− mice, and the intracellular [3H]cholesterol can be esterified to cholesteryl esters. These results provided evidence indicating that the main function of NPC1L1 is to promote cholesterol uptake from the intestinal lumen but that it is not necessary for intracellular cholesterol transport to the ER. Surprisingly, NBD-cholesterol was taken up by intestinal mucosa, esterified to NBD-cholesteryl esters, and transported to plasma circulation to similar extent between Npc1l1+/+ and Npc1l1−/− mice. Ezetimibe treatment also had no impact on NBD-cholesterol absorption by Npc1l1+/+ mice. Thus, NBD-cholesterol absorption proceeds through an NPC1L1-independent and ezetimibe-insensitive sterol absorption mechanism. Taken together, these results indicate that NBD-cholesterol can be used to trace the alternative cholesterol absorption pathway but is not suitable for tracking NPC1L1-mediated cholesterol absorption.

scholarly journals NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
D. Höglinger ◽  
T. Burgoyne ◽  
E. Sanchez-Heras ◽  
P. Hartwig ◽  
A. Colaco ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Cholesterol Transport ◽  
Cholesterol Accumulation ◽  
C Protein ◽  
Membrane Contact Sites ◽  
Sterol Transport ◽  
Membrane Contact ◽  
Mitochondrial Cholesterol ◽  
Niemann Pick ◽  
The Impact

Abstract Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells.

scholarly journals Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening

EBioMedicine ◽  
2016 ◽  
Vol 4 ◽  
pp. 170-175 ◽  
Author(s):  
Janine Reunert ◽  
Manfred Fobker ◽  
Frank Kannenberg ◽  
Ingrid Du Chesne ◽  
Maria Plate ◽  
...  
Keyword(s):  
Rapid Diagnosis ◽  
Cholesterol Transport ◽  
Type C ◽  
Niemann Pick

Effects of dietary cholesterol restriction in a feline model of Niemann-Pick type C disease

2001 ◽  
Vol 24 (4) ◽  
pp. 427-436 ◽  
Author(s):  
K. L. Somers ◽  
D. E. Brown ◽  
R. Fulton ◽  
P. C. Schultheiss ◽  
D. Hamar ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Type C ◽  
Niemann Pick ◽  
Feline Model

scholarly journals Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells

2009 ◽  
Vol 106 (46) ◽  
pp. 19316-19321 ◽  
Author(s):  
L. Abi-Mosleh ◽  
R. E. Infante ◽  
A. Radhakrishnan ◽  
J. L. Goldstein ◽  
M. S. Brown
Keyword(s):  
Endoplasmic Reticulum ◽  
C Cells ◽  
Type C ◽  
Niemann Pick

Dietary induction of pancreatic cholesterol esterase: a regulatory cycle for the intestinal absorption of cholesterol

1996 ◽  
Vol 74 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Terry Sasser ◽  
Chakradhar Buddhiraju ◽  
Vijaya B. Kumar ◽  
Angel Lopez-Candales ◽  
Jackie Grosjlos ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Cholesterol Absorption ◽  
Cholesterol Esterase ◽  
Intestinal Cholesterol Absorption ◽  
Sterol Esters ◽  
Mrna Induction ◽  
High Fraction ◽  
Dietary Sterol ◽  
Human Intestinal Cells

Atherosclerosis has a strong dietary basis without a proven molecular mechanism for cholesterol absorption. To investigate the potential role of pancreas in this process and its interaction with the two dietary forms of cholesterol (free and esterified), we undertook to study the role of pancreatic cholesterol esterase in cholesterol absorption. The results showed that (i) cholesterol esters contribute a disproportionately high fraction of absorbed dietary cholesterol, (ii) rates of intestinal cholesterol absorption are related to pancreatic cholesterol esterase activity, (iii) mRNA specific for pancreatic cholesterol esterase is induced 15-fold by dietary sterol esters and 10-fold by free sterol, (iv) the induction of cholesterol esterase mRNA is reversible, and (v) free cholesterol transport into cultured human intestinal cells is enhanced 300% by pancreatic cholesterol esterase. These data implicate pancreatic cholesterol esterase as pivotal in a metabolic loop under positive feedback control for the absorption of dietary cholesterol, whether free or esterified.Key words: cholesterol esterase, diet, transport, mRNA, induction.

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