Disease relevance of NPC1L1

• Combination therapy using a novel, specific, and potent cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and HMG-CoA reductase inhibitors (statins) offers an efficacious new approach to the prevention and treatment of hypercholesterolemia [1].
• In this study, a hepatoma cell line stably expressing human NPC1L1 was established, and cholesterol uptake was studied [2].
• Furthermore, loss of NPC1L1 expression has been shown to protect against diet-induced fatty liver [3].

High impact information on NPC1L1

• Recent research suggests that the newly identified Niemann-Pick C1-like 1 protein (NPC1L1) is expressed at the apical surface of enterocytes and plays a critical role in the absorption of intestinal cholesterol [1].
• Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels [4].
• Here, we use the NS variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (LDLs) [4].
• The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1) [5].
• Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice [5].

Biological context of NPC1L1

• Moreover, a diet enriched in n-3 fatty acids decreases the gene expression of NPC1L1 in duodenum and jejunum of hamster [6].
• The gene, named NPC1L1, was mapped to chromosome 7p13, contained 20 exons, including an unusually large 1526-bp exon 2, and spanned approximately 29 kb [7].
• In contrast to NPC1, the NPC1L1 putative promoter region contained a sterol-regulatory element [7].
• While there are many explanations for non-response to medications, our data suggest a possible relationship between NPC1L1 variation and ezetimibe response and further indicate that a non-response phenotype might ascertain subjects with genomic DNA variants that could help define metabolic pathways [8].
• We found that one non-responder to ezetimibe was a compound heterozygote for two rare non-synonymous polymorphisms in NPC1L1 that were absent in normal control subjects [8].

Anatomical context of NPC1L1

• Knockdown of NPC1L1 caused a decline in the ability of Caco-2 cells to capture micellar [(14)C]free cholesterol [9].
• The current investigation was undertaken to explore the localization and function of NPC1L1 in human enterocytes [9].
• Recent studies have documented the presence of Niemann-Pick C1-Like 1 (NPC1L1) in the small intestine and its capacity to transport cholesterol in mice and rats [9].
• Cell fractionation experiments revealed an NPC1L1 association with apical membrane of the enterocyte in human jejunum [9].
• Further characterization of cell lines generated from wild-type and knock-out mice revealed that in contrast to wild-type cells, NPC1L1 cells exhibit aberrant plasma membrane uptake and subsequent transport of various lipids, including cholesterol and sphingolipids [10].

Associations of NPC1L1 with chemical compounds

• Efforts were devoted to define the impact of NPC1L1 knockdown on other mediators of cholesterol uptake [9].
• KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively [5].
• NPC1L1, a recently identified relative of Niemann-Pick C1, was characterized to determine its subcellular location and potential function(s) [10].
• Regulation of intestinal NPC1L1 expression by dietary fish oil and docosahexaenoic acid [6].
• At steady state, NPC1L1 proteins localized predominantly to the transferrin-positive endocytic recycling compartment, where free cholesterol also accumulated as revealed by filipin staining [2].

Other interactions of NPC1L1

• Additionally, a high percentage of mutations were located at amino acids identical to the NPC1 homolog, NPC1L1 [11].
• There was a positive correlation between NPLC1L1 and MTTP mRNA (p<0.01) and a negative correlation between NPC1L1 and ABCG5 mRNA (p<0.001) [12].
• Peroxisome proliferator-activated receptor delta (PPARdelta) activation decreased NPC1L1 mRNA levels and cholesterol trafficking to the endoplasmic reticulum, suggesting that 22:6 may act through PPARdelta [6].
• Our study demonstrated the modulation of human NPC1L1 expression and promoter activity by cholesterol in a SREBP-2-dependent mechanism [13].

Analytical, diagnostic and therapeutic context of NPC1L1

• Confirmation of cellular NPC1L1 distribution was obtained by immunocytochemistry [9].
• Real-time PCR quantifications of the putative cholesterol transporter Niemann-Pick C1 like 1 (NPC1L1) mRNA revealed that, in these cell lines, the activity of cholesterol transport correlated with the level of NPC1L1 expression [14].
• Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response [15].

References