- •NPC1L1 exon 2 amino acid mutations identified in an exceptional ezetimibe responder.
- •Molecular modeling showed altered cholesterol entry and cholesterol binding.
- •Amino acid changes reduced cholesterol uptake when ezetimibe was present.
- •Major amino acids changes involved are L52P and I300T.
- •NPC1L1 protein:protein interactions are altered.
Methods and results
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- Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681
- Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.J. Lipid Res. 1993; 34: 1637-1659
- Zetia: inhibition of Niemann-Pick C1 like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia.J. Atheroscler. Thromb. 2007; 14: 99-108
- Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.Eur. Heart J. 2003; 24: 729-741
- Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.Atherosclerosis. 2007; 194: e116-e122
- Emerging roles of the intestine in control of cholesterol metabolism.World J. Gastroenterol. 2006; 12: 6429-6439
- Evidence for a Niemann–Pick C (NPC) gene family: identification and characterization of NPC1L1.Genomics. 2000; 65: 137-145
- Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204
- The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8132-8137
- In vivo responsiveness to ezetimibe correlates with Niemann-Pick C1 Like-1 (NPC1L1) binding affinity: comparison of multiple species NPC1L1 orthologs.Mol. Pharmacol. 2007; 71: 19-29
- Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine.J. Lipid Res. 2012; 53: 2092-2101
- Extracellular loop C of NPC1L1 is important for binding to ezetimibe.Proc. Natl. Acad. Sci. 2008; 105: 11140-11145
- Mining the genomes of exceptional responders.Nat. Rev. Cancer. 2014; 14: 291-292
- An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia.Nutr. Metab. Cardiovasc. Dis. 2010; 20: 236-242
- Functional characterization of genetic variants in NPC1L1 supports the sequencing extremes strategy to identify complex trait genes.Hum. Mol. Genet. 2008; 17: 2101-2107
- NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 1-5
- Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1810-1815
- In-vitro characterization of the six clustered variants of NPC1L1 observed in cholesterol low absorbers.Pharmacogenet. Genomics. 2009; 19: 884-892
- Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly.J. Lipid Res. 2010; 51: 1201-1207
- A SNP of NPC1L1 affects cholesterol absorption in Japanese.J. Atheroscler. Thromb. 2010; 17: 356-360
- Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656
- The structure of the NPC1L1 N-terminal domain in a closed conformation.PLoS One. 2011; 6: e18722
- Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.Cell. 2009; 137: 1213-1224
- Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation.J. Comput. Chem. 2002; 23: 1623-1641
- Comparison of multiple Amber force fields and development of improved protein backbone parameters.Proteins Struct. Funct. Bioinforma. 2006; 65: 712-725
- The Amber biomolecular simulation programs.J. Comput. Chem. 2005; 26: 1668-1688
- Comparison of simple potential functions for simulating liquid water.J. Chem. Phys. 1983; 79: 926
- Particle mesh Ewald: an N⋅ log (N) method for Ewald sums in large systems.J. Chem. Phys. 1993; 98: 10089
- Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes.J. Comput. Phys. 1977; 23: 327-341
- Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space.J. Chem. Inf. Model. 2007; 47: 122-133
- Enhanced sensitivity in proteomics experiments using FAIMS coupled with a hybrid linear ion trap/Orbitrap mass spectrometer.J. Proteome Res. 2009; 8: 3355-3366
- Bioinformatics meets proteomics–bridging the gap between mass spectrometry data analysis and cell biology.J. Bioinform. Comput. Biol. 2003; 1: 183-200
- The Δ>15 Kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.Clin. Genet. 2004; 65: 202-208
- Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake.Proc. Natl. Acad. Sci. 2011; 108: 551-556
- Inactivating mutations in NPC1L1 and protection from coronary heart disease.N. Engl. J. Med. 2014; 371: 2072
- IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).American Heart Association Scientific Sessions, Chicago2014
- Inactivating mutations in NPC1L1 and protection from coronary heart disease.N. Engl. J. Med. 2014; 371: 2072-2082
- Mutations in NPC1L1 and coronary heart disease.N. Engl. J. Med. 2015; 372: 881-883
- Common single nucleotide polymorphisms at the NPC1L1 gene locus significantly predict cardiovascular risk in coronary patients.Atherosclerosis. 2015; 242: 340-345
- Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.Clin. Genet. 2005; 67: 175-177
- The N-terminal domain of NPC1L1 protein binds cholesterol and plays essential roles in cholesterol uptake.J. Biol. Chem. 2011; 286: 25088-25097
- The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1.Cell Metab. 2008; 7: 508-519
- Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT.Nat. Neurosci. 2011; 14: 469-477
- A new paradigm for membrane-organizing and -shaping scaffolds.FEBS Lett. 2006; 580: 5559-5564
- The roles of flotillin microdomains – endocytosis and beyond.J. Cell Sci. 2011; 124: 3933-3940
- Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272
- A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.N. Engl. J. Med. 2014; 370: 1809-1819