Niemann-Pick C1-Like 1 inhibitors for reducing cholesterol absorption

2022 ◽  
pp. 114111
Author(s):  
Renshuai Zhang ◽  
Wenjing Liu ◽  
Jun Zeng ◽  
Jingsen Meng ◽  
Hongfei Jiang ◽  
...  
Keyword(s):  
Cholesterol Absorption ◽  
Niemann Pick

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.

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 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.

scholarly journals Multiple mechanisms limit the accumulation of unesterified cholesterol in the small intestine of mice deficient in both ACAT2 and ABCA1

2010 ◽  
Vol 299 (5) ◽  
pp. G1012-G1022 ◽  
Author(s):  
Stephen D. Turley ◽  
Mark A. Valasek ◽  
Joyce J. Repa ◽  
John M. Dietschy
Keyword(s):  
Small Intestine ◽  
Mrna Level ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
Unesterified Cholesterol ◽  
Compensatory Mechanisms ◽  
Niemann Pick ◽  
Sterol Excretion ◽  
Deficient Mice

Cholesterol homeostasis in the enterocyte is regulated by the interplay of multiple genes that ultimately determines the net amount of cholesterol reaching the circulation from the small intestine. The effect of deleting these genes, particularly acyl CoA:cholesterol acyl transferase 2 (ACAT2), on cholesterol absorption and fecal sterol excretion is well documented. We also know that the intestinal mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1) increases in Acat2−/− mice. However, none of these studies has specifically addressed how ACAT2 deficiency impacts the relative proportions of esterified and unesterified cholesterol (UC) in the enterocyte and whether the concurrent loss of ABCA1 might result in a marked buildup of UC. Therefore, the present studies measured the expression of numerous genes and related metabolic parameters in the intestine and liver of ACAT2-deficient mice fed diets containing either added cholesterol or ezetimibe, a selective sterol absorption inhibitor. Cholesterol feeding raised the concentration of UC in the small intestine, and this was accompanied by a significant reduction in the relative mRNA level for Niemann-Pick C1-like 1 (NPC1L1) and an increase in the mRNA level for both ABCA1 and ABCG5/8. All these changes were reversed by ezetimibe. When mice deficient in both ACAT2 and ABCA1 were fed a high-cholesterol diet, the increase in intestinal UC levels was no greater than it was in mice lacking only ACAT2. This resulted from a combination of compensatory mechanisms including diminished NPC1L1-mediated cholesterol uptake, increased cholesterol efflux via ABCG5/8, and possibly rapid cell turnover.

Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: role of sterol regulatory element binding protein 2

2007 ◽  
Vol 292 (1) ◽  
pp. G369-G376 ◽  
Author(s):  
Waddah A. Alrefai ◽  
Fadi Annaba ◽  
Zaheer Sarwar ◽  
Alka Dwivedi ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Absorption ◽  
Cholesterol Depletion ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Niemann Pick ◽  
Coa Reductase

Niemann-Pick C1-like 1 (NPC1L1) is an essential intestinal component of cholesterol absorption. However, little is known about the molecular regulation of intestinal NPC1L1 expression and promoter activity. We demonstrated that human NPC1L1 mRNA expression was significantly decreased by 25-hydroxycholesterol but increased in response to cellular cholesterol depletion achieved by incubation with Mevinolin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) in human intestinal Caco-2 cells. We also showed that a −1741/+56 fragment of the NPC1L1 gene demonstrated high promoter activity in Caco-2 cells that was reduced by 25-hydroxycholesterol and stimulated by cholesterol depletion. Interestingly, we showed that the NPC1L1 promoter is remarkably transactivated by the overexpression of sterol regulatory element (SRE) binding protein (SREBP)-2, suggesting its involvement in the sterol-induced alteration in NPC1L1 promoter activity. Finally, we identified two putative SREs in the human NPC1L1 promoter and established their essential roles in mediating the effects of cholesterol on promoter activity. Our study demonstrated the modulation of human NPC1L1 expression and promoter activity by cholesterol in a SREBP-2-dependent mechanism.

scholarly journals The Chylomicron: Relationship to Atherosclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Gerald H. Tomkin ◽  
Daphne Owens
Keyword(s):  
Cholesterol Synthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Structural Protein ◽  
Chylomicron Particle ◽  
Niemann Pick ◽  
Chylomicron Formation ◽  
The Relationship ◽  
Ldl Composition

The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

Association between non-responsiveness to plant sterol intervention and polymorphisms in cholesterol metabolism genes: a case-control study

2008 ◽  
Vol 33 (4) ◽  
pp. 728-734 ◽  
Author(s):  
Iwona Rudkowska ◽  
Suhad S. AbuMweis ◽  
Catherine Nicolle ◽  
Peter J.H. Jones
Keyword(s):  
Plant Sterol ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Individual Variability ◽  
Nucleotide Polymorphisms ◽  
Control Phase ◽  
Individual Variations ◽  
Niemann Pick

Plant sterol (PS) consumption decreases low-density lipoprotein cholesterol (LDL-C) levels; however, high variability of responsiveness of lipid levels to PS intervention has been observed. We hypothesized that common single-nucleotide polymorphisms (SNPs) in the genes for the ATP binding cassette proteins G5 (ABCG5) and G8 (ABCG8), Niemann-Pick C1-like 1 (NPC1L1), or other proteins of the cholesterol pathway, would underline inter-individual variations in response to PS. Twenty-six hyperlipidemic subjects completed a randomized trial of 3 PS phases and a control phase. Three non-responders were identified who failed on 3 consecutive occasions to decrease either total cholesterol or LDL-C level vs. control. It was observed that after 3 PS phases compared with a control phase, cholesterol absorption changed to a lesser degree (–7.7% ± 10.8%) in the non-responders than in the top 3 responders (–22.1% ± 8.8%); however, cholesterol synthesis rates did not differ between sub-groups. No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-responders. Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. Results indicate PS intake did not decrease cholesterol absorption rates to the same degree in certain subjects, possibly clarifying the inter-individual variability in the cholesterol-lowering effect; hence, this work should be expanded.

A silent mutation of Niemann-Pick C1-like 1 and apolipoprotein E4 modulate cholesterol absorption in primary hyperlipidemias

2013 ◽  
Vol 7 (2) ◽  
pp. 147-152 ◽  
Author(s):  
Graziana Lupattelli ◽  
Livia Pisciotta ◽  
Stefano De Vuono ◽  
Donatella Siepi ◽  
Antonella Bellocchio ◽  
...  
Keyword(s):  
Cholesterol Absorption ◽  
Silent Mutation ◽  
Apolipoprotein E4 ◽  
Niemann Pick
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