Affinage

NPC1L1

NPC1-like intracellular cholesterol transporter 1 · UniProt Q9UHC9

Length
1359 aa
Mass
148.7 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPC1L1 is a polytopic, heavily glycosylated 13-transmembrane glycoprotein that serves as the rate-limiting transporter for absorption of dietary free cholesterol at the brush border of intestinal enterocytes and the canalicular membrane of hepatocytes, where its loss abolishes intestinal sterol uptake and confers resistance to diet-induced hypercholesterolemia (PMID:15173162, PMID:19325169, PMID:15777641). Its N-terminal domain (NTD) selectively binds free cholesterol but not plant sterols, and the residue Leu-216 is required for cholesterol binding, formation of NPC1L1–flotillin–cholesterol membrane microdomains, and downstream uptake (PMID:21602275); the transporter handles non-esterified cholesterol unidirectionally and does not mediate efflux or take up esterified or plant sterols (PMID:17523925). Cholesterol loading triggers internalization of NPC1L1: binding at the NTD releases a YVNXXF motif in the cytoplasmic C-terminal tail from the membrane, allowing the clathrin adaptor Numb to engage it and recruit clathrin/AP2 for endocytosis, a step required for cholesterol uptake in vivo (PMID:18522832, PMID:24336247, PMID:22811412). The transporter cycles between the plasma membrane and a transferrin/Rab11-positive endocytic recycling compartment, with return to the cell surface driven by the myosin Vb·Rab11a·Rab11-FIP2 complex and by Cdc42 acting through N-WASP/Arp3 (PMID:16407187, PMID:19542231, PMID:21844200, PMID:18523240). Structurally, NPC1L1 functions as a homodimer assembled through transmembrane helix 2 (Trp-347), and cryo-EM of apo, cholesterol-bound, and ezetimibe-bound states shows that the sterol-sensing domain binds variable numbers of cholesterol molecules and that NTD rotation opens a continuous tunnel for sterol movement (PMID:32596471, PMID:34272236, PMID:34407950). The same intramolecular tunnel also transports vitamin K and α-tocopherol, the latter competing with cholesterol for the NTD (PMID:34407950, PMID:25696002, PMID:28315682). Ezetimibe, the direct molecular target whose binding is lost in NPC1L1-null membranes, engages an extracellular loop C site (Phe-532/Met-543) at the interface of the extracellular domains and locks the transporter in a closed conformation that occludes the tunnel without competing for cholesterol binding (PMID:15928087, PMID:18682566, PMID:32596471, PMID:32410728). Transcription is driven by SREBP2 together with HNF1α, HNF4α, and PPARα, and is repressed by SHP/FGF19 signaling and CREBH (PMID:18080173, PMID:20460578, PMID:20953676, PMID:30521806, PMID:27818935).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 High

    Established NPC1L1 as the genetically required gatekeeper of intestinal sterol entry, resolving which protein controls dietary cholesterol and phytosterol absorption.

    Evidence NPC1L1 knockout mice with intestinal cholesterol/sitosterol uptake and plasma lipid readouts

    PMID:15173162

    Open questions at the time
    • Did not establish the molecular transport mechanism or whether NPC1L1 binds sterol directly
    • Tissue of action (intestine vs liver) not yet dissected
  2. 2005 High

    Identified NPC1L1 as the direct molecular target of ezetimibe, explaining the drug's mechanism of action at the protein level.

    Evidence Radioligand binding of ezetimibe glucuronide to brush border, recombinant NPC1L1, and knockout mouse membranes

    PMID:15928087

    Open questions at the time
    • Binding site on NPC1L1 not yet mapped
    • Did not show how drug binding inhibits transport
  3. 2005 High

    Defined NPC1L1 as a cycling protein resident in the endocytic recycling compartment whose surface delivery is cholesterol-responsive and drives uptake.

    Evidence Stable hepatoma cells, filipin staining, cyclodextrin cholesterol depletion, immunofluorescence with ezetimibe inhibition; biochemical glycosylation/topology characterization

    PMID:15671032 PMID:15777641 PMID:16407187

    Open questions at the time
    • Machinery driving recycling and internalization unknown
    • Direction of sterol movement (uptake vs sensing) not yet settled
  4. 2007 Medium

    Showed NPC1L1 transport is sterol-selective, unidirectional, surface-restricted, and substrate-specific for free cholesterol, defining its functional logic.

    Evidence Stable rat hepatoma cells with sterol uptake/efflux assays and pharmacological pathway perturbations

    PMID:17523925

    Open questions at the time
    • Single-lab characterization
    • Did not identify the sterol-binding region
  5. 2008 High

    Mapped the ezetimibe binding site to extracellular loop C residues distinct from the cholesterol site, and demonstrated cholesterol drives clathrin/AP2-dependent endocytosis that ezetimibe blocks.

    Evidence Chimeric/site-directed mutagenesis with radioligand binding; live imaging with clathrin/AP2 and microfilament perturbation; genetic epistasis with ABCG5/G8 triple knockout mice

    PMID:18522832 PMID:18523240 PMID:18682566 PMID:18796403

    Open questions at the time
    • Adaptor linking cholesterol sensing to clathrin not yet identified
    • How drug binding at loop C blocks transport mechanistically unresolved
  6. 2009 High

    Solved the membrane topology and identified the recycling machinery, placing NPC1L1's sterol-sensing domain in a defined orientation and showing surface delivery requires a myosin Vb·Rab11a·Rab11-FIP2 motor complex.

    Evidence Protease protection/selective permeabilization for topology; dominant-negative perturbation of myosin Vb/Rab11a/Rab11-FIP2 with uptake readouts

    PMID:19325169 PMID:19542231

    Open questions at the time
    • Trigger coupling cholesterol depletion to motor engagement unknown
    • No atomic structure yet
  7. 2011 High

    Localized cholesterol binding to the NTD via Leu-216 and identified Cdc42/N-WASP/Arp3 as the actin-nucleating arm of NPC1L1 recycling, including in hepatocyte canalicular function.

    Evidence In vitro binding plus L216 mutagenesis with in vivo adenoviral liver expression; Co-IP, dominant-negative/siRNA, and liver-specific Cdc42 knockout mice; systematic patient variant characterization

    PMID:21189420 PMID:21602275 PMID:21844200

    Open questions at the time
    • Structural basis of NTD cholesterol recognition not resolved
    • How oxysterols compete at the NTD structurally unknown
  8. 2013 High

    Identified Numb as the adaptor that couples NTD cholesterol binding to clathrin internalization via the YVNXXF tail motif, completing the endocytic recruitment pathway.

    Evidence Endocytic-signal mutagenesis, reciprocal Co-IP, intestine-specific Numb knockout mice, organoid uptake assays

    PMID:24336247

    Open questions at the time
    • Structural detail of the YVNXXF–Numb interface unknown
    • Whether Numb is the sole adaptor not addressed
  9. 2015 High

    Extended NPC1L1 substrate range to vitamin K, linking the transporter to anticoagulant pharmacology.

    Evidence Overexpression uptake, Npc1l1 knockout mice, ezetimibe+warfarin co-dosing, clinical data

    PMID:25696002

    Open questions at the time
    • Whether vitamin K uses the same tunnel as cholesterol not yet structurally shown
    • Binding site for vitamin K undefined
  10. 2017 Medium

    Showed α-tocopherol (vitamin E) is an NTD-dependent NPC1L1 substrate that competes with cholesterol and triggers the same endocytic cycle.

    Evidence NPC1L1ΔNTD cell lines, NTD competition binding, live-cell endocytosis imaging with ezetimibe inhibition

    PMID:28315682

    Open questions at the time
    • Single-lab finding
    • Physiological contribution of NPC1L1 to vitamin E status in vivo not addressed here
  11. 2020 High

    Provided the structural mechanism: cryo-EM and engineered disulfides showed NTD rotation opens a transport tunnel and that ezetimibe occludes the tunnel at the extracellular-domain interface rather than competing for cholesterol.

    Evidence Cryo-EM of apo and ezetimibe-bound NPC1L1; engineered disulfide constraints with lysosomal cholesterol efflux assays

    PMID:32410728 PMID:32596471

    Open questions at the time
    • Cholesterol-bound intermediate not resolved in this study
    • How the tunnel connects to the membrane-to-cytoplasm uptake step unclear
  12. 2021 High

    Refined the structural model with cholesterol-bound states and established that NPC1L1 functions as a TM2-mediated homodimer using a single tunnel shared by cholesterol and vitamin E.

    Evidence Multiple cryo-EM structures (apo, cholesterol-enriched, ezetimibe-bound), Trp-347 dimerization mutagenesis, functional uptake assays

    PMID:34272236 PMID:34407950

    Open questions at the time
    • Functional role of dimerization in vivo not tested
    • Path of sterol from tunnel into the cell still incomplete
  13. 2022 Medium

    Extended NPC1L1 biology beyond classical sterol absorption by showing NRF2-driven NPC1L1 expression mediates vitamin E uptake to protect drug-tolerant cancer cells from oxidative stress.

    Evidence RNA-seq, ezetimibe inhibition in MDR cells, NRF2 ChIP/promoter mapping, DNA methylation analysis, in vivo tumor model

    PMID:35023619

    Open questions at the time
    • Single-lab finding
    • Generality across cancer types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether NPC1L1-mediated sterol uptake is fundamentally endocytosis-dependent or can proceed at the cell surface remains unresolved, as does how the transport tunnel delivers sterol into the cell.
  • Endocytosis-dependent vs surface-transport models not reconciled
  • Mechanism coupling tunnel opening to net cellular cholesterol gain undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008289 lipid binding 3 GO:0140299 molecular sensor activity 2
Localization
GO:0005768 endosome 4 GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1430728 Metabolism 2
Partners
CDC42FLOTILLINMYO5BNUMBRAB11ARAB11FIP2
Complex memberships
NPC1L1 homodimerNPC1L1-flotillin-cholesterol microdomain

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 NPC1L1 is the direct molecular target of ezetimibe. Labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to HEK293 cells expressing NPC1L1; binding affinities to recombinant NPC1L1 are virtually identical to those for native enterocyte membranes; ezetimibe no longer binds membranes from NPC1L1 knockout mice. Radioligand binding assay with labeled ezetimibe glucuronide in brush border membranes, recombinant NPC1L1-expressing cells, and NPC1L1 knockout mouse membranes Proceedings of the National Academy of Sciences of the United States of America High 15928087
2004 NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols. NPC1L1 null mice show substantially reduced intestinal uptake of cholesterol and sitosterol, dramatically reduced plasma phytosterol levels, and complete resistance to diet-induced hypercholesterolemia. NPC1L1 knockout mouse model with measurements of intestinal cholesterol and phytosterol uptake, plasma lipoprotein profiles, and gene expression analysis The Journal of biological chemistry High 15173162
2008 Cholesterol specifically promotes the internalization of NPC1L1 via clathrin/AP2-mediated endocytosis requiring microfilaments. Ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles, thereby inhibiting cholesterol uptake. Blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization. Live cell imaging, clathrin/AP2 complex perturbation, microfilament disruption, cholesterol uptake assays in cultured cells Cell metabolism High 18522832
2005 At steady state, NPC1L1 localizes predominantly to the transferrin-positive endocytic recycling compartment. Acute cholesterol depletion stimulates relocation of NPC1L1 to the plasma membrane (preferentially to an apical-like subdomain), and this translocation is associated with a marked increase in cellular cholesterol uptake that is inhibited by ezetimibe. Stable hepatoma cell line expressing human NPC1L1; filipin staining; methyl-β-cyclodextrin cholesterol depletion; immunofluorescence; dose-dependent ezetimibe inhibition assay The Journal of biological chemistry High 16407187
2011 The N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue Leu-216 eliminates cholesterol binding, decreases formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in cultured cells and mouse livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols. 25- or 27-hydroxycholesterol competes with cholesterol for NTD binding and inhibits cholesterol-induced endocytosis of NPC1L1. In vitro cholesterol binding assay, site-directed mutagenesis (L216 mutation), adenovirus-mediated expression in mouse liver, cholesterol uptake assays, competition assays with oxysterols The Journal of biological chemistry High 21602275
2013 The clathrin adaptor Numb recognizes an endocytic peptide signal YVNXXF in the cytoplasmic C-terminal tail of NPC1L1. Cholesterol binding on the NTD releases this YVNXXF-containing region from association with the plasma membrane, enabling Numb binding. Numb recruits clathrin for internalization. Disrupting the NPC1L1-Numb interaction decreases cholesterol uptake; intestine-specific ablation of Numb in mice significantly reduces dietary cholesterol absorption and plasma cholesterol. Identification of endocytic signal by mutagenesis; Co-IP of NPC1L1 with Numb; intestine-specific Numb knockout mice; cholesterol absorption and plasma cholesterol measurements; intestinal organoid cholesterol uptake assays Nature medicine High 24336247
2009 Transport of NPC1L1 from the endocytic recycling compartment to the plasma membrane requires the microfilament-associated myosin Vb·Rab11a·Rab11-FIP2 triple complex. Inactivation of any component of this complex (by dominant-negative mutants) inhibits NPC1L1 export to the cell surface and decreases cholesterol uptake. Dominant-negative mutant expression of myosin Vb, Rab11a, and Rab11-FIP2; pharmacological microfilament disruption; NPC1L1 trafficking and cholesterol uptake assays The Journal of biological chemistry High 19542231
2008 Ezetimibe binds to NPC1L1 at a site within a 61-aa region of extracellular loop C; Phe-532 and Met-543 in loop C are key contributors to high-affinity binding of ezetimibe analogs. The binding site resides in the intestinal lumen. EZE binding to this extracellular site (distinct from where cholesterol binds at loop A/NTD) may prevent conformational changes in NPC1L1 necessary for cholesterol translocation. Proteomic identification of NPC1L1 as ezetimibe-binding protein; chimeric and site-directed mutagenesis studies with radioligand [³H]AS; species (mouse vs. dog) binding affinity comparisons Proceedings of the National Academy of Sciences of the United States of America High 18682566
2009 Human NPC1L1 contains 13 transmembrane helices with the NH2-terminus in the lumen and the COOH-terminus projecting to the cytosol, with seven small cytoplasmic loops and four small and three large luminal loops. The putative sterol-sensing domain is oriented similarly to those of HMGCR, NPC1, and SCAP. Protease protection assays and immunofluorescence in selectively permeabilized cells expressing human NPC1L1 Journal of lipid research High 19325169
2020 Cryo-EM structures of NPC1L1 in apo and ezetimibe-bound forms reveal that: (1) the apo (open) state has the NTD loosely associated, leaving the NTD central cavity accessible for cholesterol loading; (2) in the ezetimibe-bound (closed) state, the NTD rotates ~60°, creating a continuous tunnel for cholesterol movement into the plasma membrane; (3) ezetimibe blocks cholesterol transport by occluding the tunnel rather than competing with cholesterol binding. Cryo-electron microscopy structure determination of apo and ezetimibe-bound NPC1L1 Science advances High 32596471
2021 Cryo-EM structures of human NPC1L1 in apo, cholesterol-enriched, and ezetimibe-bound states show that the sterol-sensing domain (SSD) responds to cholesterol level by binding different numbers of cholesterol molecules; increasing cholesterol triggers formation of a stable structural cluster in SSD, while ezetimibe binding deforms the SSD and destroys this cluster, inhibiting NPC1L1 function. Cryo-electron microscopy structure determination of three NPC1L1 states (apo, cholesterol-enriched, ezetimibe-bound) Science advances High 34272236
2021 Human NPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues within transmembrane helix 2 (including Trp-347) that has a horizontal orientation in the membrane. Mutation of Trp-347 disrupts dimerization and the resulting monomeric NPC1L1 exhibits reduced efficiency of cholesterol uptake. The same intramolecular channel mediates transport of both vitamin E and cholesterol. Cryo-EM structures of hNPC1L1 bound to cholesterol or vitamin E analog; site-directed mutagenesis of Trp-347; functional cholesterol uptake assays of monomeric vs. dimeric NPC1L1 Science advances High 34407950
2012 In mouse small intestine in vivo, NPC1L1 is localized on the brush border of enterocytes in the absence of cholesterol. Dietary cholesterol induces internalization of NPC1L1 to the subapical layer beneath the brush border, partially colocalizing with the endosome marker Rab11. Ezetimibe blocks internalization of NPC1L1 and cholesterol, causing their retention in the plasma membrane. Immunofluorescence and confocal microscopy of mouse small intestine sections after dietary cholesterol feeding with and without ezetimibe treatment Journal of lipid research High 22811412
2011 The small GTPase Cdc42 interacts with NPC1L1. Cholesterol depletion activates Cdc42 and enhances NPC1L1-Cdc42 interaction. Constitutively active or dominant-negative Cdc42, as well as knockdown of downstream effectors N-WASP or Arp3, inhibits NPC1L1 transport to the plasma membrane. In liver-specific Cdc42 knockout mice, NPC1L1 fails to localize to bile canaliculi and biliary cholesterol cannot be efficiently reabsorbed. Co-IP of NPC1L1 with Cdc42; dominant-negative and constitutively active Cdc42 mutant expression; siRNA knockdown of N-WASP and Arp3; liver-specific Cdc42 knockout mice with biliary cholesterol reabsorption assay The Journal of biological chemistry High 21844200
2015 NPC1L1 plays a central role in intestinal vitamin K (VK) absorption. In vitro NPC1L1 overexpression increases VK uptake; Npc1l1 knockout mice show reduced intestinal VK absorption; ezetimibe inhibits VK absorption and reduces hepatic VK levels, enhancing the pharmacological effect of warfarin. NPC1L1-overexpressing intestinal cells (in vitro VK uptake); Npc1l1 knockout mice (in vivo VK absorption); ezetimibe+warfarin co-administration studies in mice; retrospective clinical data analysis Science translational medicine High 25696002
2017 The NTD of NPC1L1 is essential for α-tocopherol (vitamin E) transport. α-Tocopherol promotes NPC1L1 endocytosis in an NTD-dependent manner; α-tocopherol competitively binds NPC1L1-NTD with cholesterol. Cells expressing NPC1L1 lacking the NTD (NPC1L1ΔNTD) cannot undergo α-tocopherol-induced endocytosis. Ezetimibe prevents α-tocopherol-induced endocytosis of NPC1L1. NPC1L1-GFP and NPC1L1ΔNTD-GFP stable cell lines; competition binding assay for NTD; live cell imaging of endocytosis; ezetimibe inhibition Biochemical and biophysical research communications Medium 28315682
2005 NPC1L1 localizes in a vesicular subcellular compartment rich in the small GTPase Rab5 in HepG2 cells. NPC1L1 null mouse cells exhibit aberrant plasma membrane uptake and transport of cholesterol and sphingolipids, and a deregulation of caveolin transport and localization. Subcellular fractionation and colocalization with Rab5; NPC1L1 knockout-derived cell lines with lipid transport and caveolin localization assays The Journal of biological chemistry Medium 15671032
2005 Native and recombinant rat NPC1L1 is a ~145 kDa, highly glycosylated membrane protein enriched in the brush border membrane of intestinal enterocytes. Recombinant NPC1L1 expressed in CHO cells shows cell surface expression. Sequential detergent extraction of enterocytes, SDS-PAGE/Western blot, glycosylation analysis, expression of Flag-tagged NPC1L1 in CHO cells with cell surface detection Biochimica et biophysica acta Medium 15777641
2007 NPC1L1 mediates sterol-specific, unidirectional transport of non-esterified (free) cholesterol only when located at the cell surface. NPC1L1 does not affect uptake of esterified cholesterol or β-sitosterol (plant sterol), and does not promote cellular cholesterol efflux. NPC1L1-dependent cholesterol uptake requires adequate intracellular K⁺ but not Ca²⁺, cytoskeleton, or signaling downstream of PKA, PKC, or pertussis toxin-sensitive G-protein-coupled receptors. McArdle-RH7777 rat hepatoma cells stably expressing NPC1L1; sterol uptake assays with free vs. esterified cholesterol and plant sterols; cholesterol efflux assays; pharmacological perturbations of signaling pathways The Biochemical journal Medium 17523925
2008 Kinetic imaging (FRAP) shows that ~42% of NPC1L1 resides in the transferrin-positive endocytic recycling compartment (ERC) at steady state with rapid recovery half-time of ~2.5 min. Acute cholesterol depletion blocks internalization of NPC1L1-EGFP and stimulates recycling from the ERC to the plasma membrane. NPC1L1-EGFP facilitates fluorescent sterol transport from the plasma membrane to the ERC. In polarized hepatoma cells, NPC1L1 localizes almost exclusively to the canalicular membrane. Insulin induces translocation of NPC1L1-containing vesicles from the ERC to the cell membrane. Live imaging, FRAP, NPC1L1-EGFP trafficking assays, fluorescent cholesterol analogs, cholesterol depletion, insulin treatment, cell polarization Journal of lipid research Medium 18523240
2007 HNF4α is a crucial modulator of NPC1L1 transcription. HNF4α knockdown reduces NPC1L1 expression and cholesterol-dependent regulation. Binding sites for HNF4α are located at -209 to -197 and -52 to -40 in the human NPC1L1 promoter. SREBP2 and HNF4α cooperate to regulate NPC1L1 transcription. Reporter gene (luciferase) assays with NPC1L1 promoter constructs, EMSA, siRNA knockdown of HNF4α in intestinal cells Pharmaceutical research Medium 18080173
2010 SREBP2 and HNF1α are important regulators of NPC1L1 in human liver. SREBP2 dose-dependently regulates NPC1L1 promoter activity and mRNA; ChIP confirms SREBP2 binding to the NPC1L1 promoter in vivo. HNF1α (not HNF4α) increases NPC1L1 promoter activity and gene expression; a functional HNF1 binding site is identified in the NPC1L1 promoter, confirmed by ChIP. Luciferase reporter assays in HuH7 cells; ChIP for SREBP2 and HNF1α; correlation analysis in human liver biopsies; deletion mutant promoter constructs Journal of lipid research Medium 20460578
2010 PPARα positively regulates human NPC1L1 transcription via direct binding to a PPRE at -846/-834 in the NPC1L1 promoter, confirmed by EMSA with PPARα and RXRα. PPARα-specific knockdown significantly decreases endogenous NPC1L1 mRNA and protein in HepG2 cells. PGC1α stimulates SREBP2/HNF4α- and PPARα/RXRα-mediated activation of the NPC1L1 promoter. Reporter gene assays with PPARα-response element deletion/mutation constructs; EMSA with PPARα and RXRα; siRNA knockdown of PPARα in HepG2 cells Pharmaceutical research Medium 20953676
2018 Small Heterodimer Partner (SHP/NR0B2) and postprandial FGF19 signaling inhibit intestinal NPC1L1 expression and reduce cholesterol absorption. FGF19 signaling leads to phosphorylation of SHP, which inhibits SREBP2 activity, thereby repressing NPC1L1 transcription. These effects were absent in SHP-knockout and FGF15-knockout mice. SHP-knockout and FGF15-knockout mice; FGF19 injection in mice; luciferase reporter assays in HT29 cells; intestinal organoids; fractional cholesterol absorption measurement; RNA-seq Gastroenterology Medium 30521806
2016 CREBH directly regulates Npc1l1 expression as shown by promoter assays. Intestinal CREBH overexpression in mice reduces NPC1L1 mRNA and protein, decreasing cholesterol absorption; CREBH null mice exhibit higher intestinal NPC1L1 expression and elevated plasma/hepatic cholesterol. CREBH transgenic and knockout mice; NPC1L1 expression analysis; promoter luciferase assays; cholesterol absorption and fecal output measurements Molecular metabolism Medium 27818935
2020 Inter-domain dynamics are required for NPC1L1-mediated cholesterol transport. Introduction of single disulfide bonds to constrain lumenal/extracellular domains or shortening a cytoplasmic loop abolishes NPC1L1 transport activity. Ezetimibe's binding site lies at the interface between NPC1L1's three extracellular domains, blocking transport by binding to multiple domains simultaneously. Single disulfide bond introduction into NPC1L1; lysosomal cholesterol efflux assay; cytoplasmic loop shortening mutants; ezetimibe binding site mapping by disulfide crosslinking eLife Medium 32410728
2018 NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains. GM3 synthase (GM3S)-deficient cells show impaired NPC1L1-dependent cholesterol uptake. GM3S deficiency in mice promotes resistance to diet-induced hypercholesterolemia. GM3S-deficient cell model; NPC1L1-dependent cholesterol uptake assay; wild-type and apoE-deficient mice on normal or high-cholesterol diets Journal of lipid research Medium 30242108
2011 Multiple NPC1L1 non-synonymous variants from cholesterol low absorbers show dysfunction in cholesterol uptake due to impaired recycling, subcellular localization, glycosylation, or stability. Severely dysfunctional variants are rapidly degraded through the ER-associated degradation (ERAD) pathway. In vivo (adenoviral expression in mouse liver), the S881L variant failed to localize to liver canalicular membrane, causing defects in biliary cholesterol re-absorption. Expression of 19 NPC1L1 NS variants in cultured cells; cholesterol uptake assays; subcellular localization; glycosylation analysis; protein stability assay; adenovirus-mediated liver expression in mice The Journal of biological chemistry Medium 21189420
2022 NPC1L1 mediates uptake of vitamin E in drug-tolerant persister (DTP) cancer cells to prevent chemotherapy-triggered oxidative stress. NRF2 transcriptionally regulates NPC1L1 by binding to the -205 to -215 bp site on its promoter; decreased DNA methylation also contributes to NPC1L1 expression in this context. RNA-seq of DTP cancer cells; NPC1L1 inhibition by ezetimibe in MDR cancer cells; ChIP/promoter assay identifying NRF2 binding site; DNA methylation analysis; in vivo tumor model EMBO molecular medicine Medium 35023619
2008 NPC1L1 is required for phytosterols to enter the body. In mice lacking both ABCG5/G8 and NPC1L1 (triple knockout), phytosterols do not accumulate in plasma and liver, despite ABCG5/G8 deficiency, demonstrating genetic epistasis: NPC1L1 acts upstream of ABCG5/G8 in phytosterol entry. Triple knockout mice (NPC1L1⁻/⁻ × ABCG5/G8⁻/⁻) with plasma phytosterol, hepatic cholesterol, and fecal cholesterol measurements; genetic epistasis analysis Journal of lipid research Medium 18796403
2011 Knockdown of NPC1L1 in Caco-2 cells reduces the ability to capture micellar free cholesterol. NPC1L1 suppression results in increased HMG-CoA reductase mRNA and activity, decreased ACAT activity, and increased SREBP expression, and a significant decrease in SR-BI mRNA expression with no changes in ABCA1, ABCG5, or CD36. NPC1L1 knockdown in Caco-2 cells; [¹⁴C]free cholesterol uptake assay; mRNA and activity measurements of HMG-CoA reductase, ACAT; Western blot/RT-PCR for SREBP, SR-BI, other transporters Journal of lipid research Medium 16829661
2016 Ezetimibe-sensitive cholesterol uptake by NPC1L1 does not require endocytosis. Cell surface biotinylation shows ezetimibe does not alter the rate of NPC1L1-GFP endocytosis under normal conditions. Endocytosis does not require cholesterol binding to NPC1L1's NTD. Two small-molecule inhibitors of general endocytosis failed to inhibit ezetimibe-sensitive [³H]cholesterol uptake from taurocholate micelles. Cell surface biotinylation assay; pharmacological inhibitors of endocytosis; [³H]cholesterol uptake from micelles in rat hepatocytes; NPC1L1-GFP endocytosis monitoring Molecular biology of the cell Medium 27075173

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proceedings of the National Academy of Sciences of the United States of America 579 15928087
2004 Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. The Journal of biological chemistry 536 15173162
2014 Inactivating mutations in NPC1L1 and protection from coronary heart disease. The New England journal of medicine 348 25390462
2015 Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. Journal of the American College of Cardiology 335 25770315
2008 The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell metabolism 287 18522832
2011 Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annual review of physiology 276 20809793
2005 Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. The Journal of biological chemistry 226 15671032
2005 Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. The Journal of nutrition 224 16177187
2000 Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics 174 10783261
2005 Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake. The Journal of biological chemistry 168 16407187
2004 Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. Journal of lipid research 152 15604518
2010 NPC1L1 and cholesterol transport. FEBS letters 146 20307540
2006 Localization and role of NPC1L1 in cholesterol absorption in human intestine. Journal of lipid research 128 16829661
2009 Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter. Biochimica et biophysica acta 111 19272334
2005 Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment. Genomics 100 16297596
2008 Extracellular loop C of NPC1L1 is important for binding to ezetimibe. Proceedings of the National Academy of Sciences of the United States of America 93 18682566
2008 Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1-/- mice. American journal of physiology. Gastrointestinal and liver physiology 93 18718999
2011 The N-terminal domain of NPC1L1 protein binds cholesterol and plays essential roles in cholesterol uptake. The Journal of biological chemistry 92 21602275
2007 Fenofibrate reduces intestinal cholesterol absorption via PPARalpha-dependent modulation of NPC1L1 expression in mouse. Journal of lipid research 91 17726195
2013 The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1. Nature medicine 89 24336247
2010 Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men. Journal of lipid research 85 21123766
2010 Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression. Lipids in health and disease 76 20403165
2022 Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy. EMBO molecular medicine 75 35023619
2015 NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Science translational medicine 75 25696002
2016 Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free radical biology & medicine 74 27634173
2015 Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease. European heart journal 74 25841872
2005 Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects. American journal of physiology. Gastrointestinal and liver physiology 73 16179600
2005 Characterization of the putative native and recombinant rat sterol transporter Niemann-Pick C1 Like 1 (NPC1L1) protein. Biochimica et biophysica acta 67 15777641
2020 Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition. Science advances 65 32596471
2018 Ezetimibe, a NPC1L1 inhibitor, attenuates neuronal apoptosis through AMPK dependent autophagy activation after MCAO in rats. Experimental neurology 64 29852178
2012 Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. Journal of lipid research 57 22811412
2009 Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption. Journal of lipid research 57 19325169
2009 Requirement of myosin Vb.Rab11a.Rab11-FIP2 complex in cholesterol-regulated translocation of NPC1L1 to the cell surface. The Journal of biological chemistry 57 19542231
2008 Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters. American journal of physiology. Gastrointestinal and liver physiology 57 18718997
2006 NPC1L1: evolution from pharmacological target to physiological sterol transporter. Arteriosclerosis, thrombosis, and vascular biology 56 16973966
2021 Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake. Science advances 52 34272236
2010 Molecular characterization of the NPC1L1 variants identified from cholesterol low absorbers. The Journal of biological chemistry 52 21189420
2007 HNF4alpha is a crucial modulator of the cholesterol-dependent regulation of NPC1L1. Pharmaceutical research 51 18080173
2018 Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption. Gastroenterology 50 30521806
2009 Polyunsaturated fatty acids down-regulate in vitro expression of the key intestinal cholesterol absorption protein NPC1L1: no effect of monounsaturated nor saturated fatty acids. The Journal of nutritional biochemistry 50 19443194
2008 Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8. Journal of lipid research 50 18796403
2005 Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clinical genetics 50 15679830
2008 Functional characterization of genetic variants in NPC1L1 supports the sequencing extremes strategy to identify complex trait genes. Human molecular genetics 49 18413323
2009 Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly. Journal of lipid research 48 19752398
2008 Genetic variation in ABC G5/G8 and NPC1L1 impact cholesterol response to plant sterols in hypercholesterolemic men. Lipids 45 18850127
2006 Regulation of intestinal NPC1L1 expression by dietary fish oil and docosahexaenoic acid. Journal of lipid research 45 17114806
2019 Diosgenin regulates cholesterol metabolism in hypercholesterolemic rats by inhibiting NPC1L1 and enhancing ABCG5 and ABCG8. Biochimica et biophysica acta. Molecular and cell biology of lipids 44 31054325
2010 HNF1alpha and SREBP2 are important regulators of NPC1L1 in human liver. Journal of lipid research 44 20460578
2007 Multiple plasma membrane receptors but not NPC1L1 mediate high-affinity, ezetimibe-sensitive cholesterol uptake into the intestinal brush border membrane. Biochimica et biophysica acta 43 17689140
2015 NPC1L1 knockout protects against colitis-associated tumorigenesis in mice. BMC cancer 42 25881076
2007 NPC1L1 (Niemann-Pick C1-like 1) mediates sterol-specific unidirectional transport of non-esterified cholesterol in McArdle-RH7777 hepatoma cells. The Biochemical journal 42 17523925
2022 Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer. Breast cancer research : BCR 40 35151363
2008 Ezetimibe blocks internalization of the NPC1L1/cholesterol complex. Cell metabolism 39 18522826
2008 Kinetic imaging of NPC1L1 and sterol trafficking between plasma membrane and recycling endosomes in hepatoma cells. Journal of lipid research 38 18523240
2008 Cholesterol homeostasis by the intestine: lessons from Niemann-Pick C1 Like 1 [NPC1L1). Atherosclerosis. Supplements 38 18585981
2016 Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression. Molecular metabolism 37 27818935
2011 SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin. American journal of physiology. Gastrointestinal and liver physiology 36 21527728
2013 Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol. Journal of lipid research 32 23482652
2010 Human NPC1L1 expression is positively regulated by PPARα. Pharmaceutical research 32 20953676
2021 Lactobacillus mediates the expression of NPC1L1, CYP7A1, and ABCG5 genes to regulate cholesterol. Food science & nutrition 31 34925816
2016 Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases. Current medicinal chemistry 31 26923679
2011 The small GTPase Cdc42 interacts with Niemann-Pick C1-like 1 (NPC1L1) and controls its movement from endocytic recycling compartment to plasma membrane in a cholesterol-dependent manner. The Journal of biological chemistry 31 21844200
2020 Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins. eLife 30 32410728
2011 Barley intake induces bile acid excretion by reduced expression of intestinal ASBT and NPC1L1 in C57BL/6J mice. Journal of agricultural and food chemistry 30 21591702
2009 In-vitro characterization of the six clustered variants of NPC1L1 observed in cholesterol low absorbers. Pharmacogenetics and genomics 30 19823104
2016 Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis. Molecular biology of the cell 29 27075173
2012 Modulation of lipid metabolism with the overexpression of NPC1L1 in mouse liver. Journal of lipid research 29 22891292
2014 The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice. Endocrinology 27 24773344
2016 Amelioration of non-alcoholic fatty liver disease with NPC1L1-targeted IgY or n-3 polyunsaturated fatty acids in mice. Metabolism: clinical and experimental 26 27923447
2008 Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and biophysical research communications 26 19071091
2021 Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption. Science advances 25 34407950
2019 Identification of a Novel Potential Probiotic Lactobacillus plantarum FB003 Isolated from Salted-Fermented Shrimp and its Effect on Cholesterol Absorption by Regulation of NPC1L1 and PPARα. Probiotics and antimicrobial proteins 24 30229515
2009 Diosgenin stimulation of fecal cholesterol excretion in mice is not NPC1L1 dependent. Journal of lipid research 24 19141868
2015 Combination of curcumin and piperine prevents formation of gallstones in C57BL6 mice fed on lithogenic diet: whether NPC1L1/SREBP2 participates in this process? Lipids in health and disease 23 26335572
2021 Lycopene Reduces Cholesterol Absorption and Prevents Atherosclerosis in ApoE-/- Mice by Downregulating HNF-1α and NPC1L1 Expression. Journal of agricultural and food chemistry 22 34428895
2019 Identification of hepatic NPC1L1 as an NAFLD risk factor evidenced by ezetimibe-mediated steatosis prevention and recovery. FASEB bioAdvances 22 32123832
2020 NPC1L1 and ABCG5/8 induction explain synergistic fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists. Molecular and cellular biochemistry 21 32661772
2014 Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. Atherosclerosis 21 25463095
2009 An NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia. Nutrition, metabolism, and cardiovascular diseases : NMCD 21 19747803
2008 Madin-Darby canine kidney II cells: a pharmacologically validated system for NPC1L1-mediated cholesterol uptake. Molecular pharmacology 21 18187582
2008 NPC1L1 and SR-BI are involved in intestinal cholesterol absorption from small-size lipid donors. Lipids 21 18373109
2018 NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains. Journal of lipid research 20 30242108
2010 A SNP of NPC1L1 affects cholesterol absorption in Japanese. Journal of atherosclerosis and thrombosis 20 20379057
2008 The role of Niemann-Pick C1 - Like 1 (NPC1L1) in intestinal sterol absorption. Journal of clinical lipidology 20 18496605
2023 Curcumin protects against high-fat diet-induced nonalcoholic simple fatty liver by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway in hamsters. The Journal of nutritional biochemistry 19 37307885
2017 N-terminal domain of the cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) is essential for α-tocopherol transport. Biochemical and biophysical research communications 19 28315682
2010 Oleic acid decreases the expression of a cholesterol transport-related protein (NPC1L1) by the induction of endoplasmic reticulum stress in CaCo-2 cells. Journal of physiology and biochemistry 19 21181463
2023 Chlorogenic acid regulates the expression of NPC1L1 and HMGCR through PXR and SREBP2 signaling pathways and their interactions with HSP90 to maintain cholesterol homeostasis. Phytomedicine : international journal of phytotherapy and phytopharmacology 18 38103317
2015 Orlistat limits cholesterol intestinal absorption by Niemann-pick C1-like 1 (NPC1L1) inhibition. European journal of pharmacology 18 26048312
2011 Microalga decreases plasma cholesterol by down-regulation of intestinal NPC1L1, hepatic LDL receptor, and HMG-CoA reductase. Journal of agricultural and food chemistry 18 21561085
2022 The role of NPC1L1 in cancer. Frontiers in pharmacology 17 36034854
2019 Pathophysiological importance of bile cholesterol reabsorption: hepatic NPC1L1-exacerbated steatosis and decreasing VLDL-TG secretion in mice fed a high-fat diet. Lipids in health and disease 17 31883528
2009 The g.-762T>C polymorphism of the NPC1L1 gene is common in Chinese and contributes to a higher promoter activity and higher serum cholesterol levels. Journal of human genetics 17 19265861
2007 Human NPC1L1 and NPC1 can functionally substitute for the ncr genes to promote reproductive development in C. elegans. Biochimica et biophysica acta 17 17662536
2018 Effect of potential probiotic Leuconostoc mesenteroides FB111 in prevention of cholesterol absorption by modulating NPC1L1/PPARα/SREBP-2 pathways in epithelial Caco-2 cells. International microbiology : the official journal of the Spanish Society for Microbiology 16 30810991
2016 Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 assimilate cholesterol and modulate ABCA1, CD36, NPC1L1 and SCARB1 in vitro. Beneficial microbes 16 27903090
2011 Novel role of NPC1L1 in the regulation of hepatic metabolism: potential contribution of ezetimibe in NAFLD/NASH treatment. Current vascular pharmacology 16 21044016
2023 CM3-SII polysaccharide obtained from Cordyceps militaris ameliorates hyperlipidemia in heterozygous LDLR-deficient hamsters by modulating gut microbiota and NPC1L1 and PPARα levels. International journal of biological macromolecules 15 37011745
2019 Selective Ah receptor modulators attenuate NPC1L1-mediated cholesterol uptake through repression of SREBP-2 transcriptional activity. Laboratory investigation; a journal of technical methods and pathology 15 31417158
2013 Effect of garlic extract on some serum biochemical parameters and expression of npc1l1, abca1, abcg5 and abcg8 genes in the intestine of hypercholesterolemic mice. Indian journal of biochemistry & biophysics 15 24772974

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