Affinage

NPC1L1

NPC1-like intracellular cholesterol transporter 1 · UniProt Q9UHC9

Length
1359 aa
Mass
148.7 kDa
Annotated
2026-04-29
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPC1L1 is a polytopic transmembrane glycoprotein that serves as the critical intestinal and hepatic transporter for free cholesterol, phytosterols, vitamin K, and vitamin E (PMID:15173162, PMID:18585981, PMID:25696002, PMID:28315682). The N-terminal domain (NTD) directly binds cholesterol, triggering clathrin/AP2-mediated endocytosis via release of a cytoplasmic YVNXXF motif that recruits the adaptor Numb; NPC1L1 then cycles between the plasma membrane and an endocytic recycling compartment through a myosin Vb–Rab11a–Rab11-FIP2 complex on microfilaments, with Cdc42 governing recycling directionality (PMID:21602275, PMID:24336247, PMID:19542231, PMID:21844200). Cryo-EM structures reveal that in the apo state the NTD cavity is accessible for cholesterol loading, whereas ezetimibe binds at an inter-domain interface including extracellular loop C residues Phe-532 and Met-543, rotating the NTD ~60° to occlude an intramolecular cholesterol transport tunnel and lock the protein in a closed, transport-incompetent conformation (PMID:32596471, PMID:34272236, PMID:18682566). Transcription of NPC1L1 is positively regulated by SREBP2, HNF1α, HNF4α, and PPARα, and negatively regulated by postprandial FGF19–SHP signaling that represses SREBP2 activity (PMID:20460578, PMID:18080173, PMID:20953676, PMID:30521806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Medium

    Identification of NPC1L1 as a paralog of NPC1 with a putative sterol-sensing domain and sterol-regulatory promoter element established a candidate cholesterol transporter gene before any functional data existed.

    Evidence EST database mining, full-length cDNA cloning, and genomic characterization

    PMID:10783261

    Open questions at the time
    • No functional data or expression pattern at this stage
    • Predicted cholesterol role based solely on sequence homology
  2. 2004 High

    Knockout mice demonstrated that NPC1L1 is essential for intestinal absorption of both cholesterol and phytosterols, converting it from a bioinformatic candidate to a validated sterol transporter.

    Evidence NPC1L1 knockout mice with cholesterol and phytosterol absorption measurements

    PMID:15173162

    Open questions at the time
    • Mechanism of transport unknown
    • Subcellular localization in native tissue not determined
    • Whether NPC1L1 directly binds sterols not established
  3. 2005 High

    Demonstration that ezetimibe binds directly and specifically to NPC1L1 — abolished in KO membranes — identified the molecular target of this clinically important drug and established a pharmacological tool for studying NPC1L1 function.

    Evidence Radioligand binding with [³H]ezetimibe glucuronide on brush border membranes, recombinant cells, and NPC1L1 KO membranes

    PMID:15928087

    Open questions at the time
    • Ezetimibe binding site on NPC1L1 not mapped
    • Mechanism by which ezetimibe blocks transport unknown
  4. 2005 High

    Discovery that cholesterol depletion drives NPC1L1 from an endocytic recycling compartment to the plasma membrane established the cholesterol-regulated endocytic recycling model as the core mechanism controlling NPC1L1 activity.

    Evidence Immunofluorescence with methyl-β-cyclodextrin depletion and ezetimibe inhibition in stable NPC1L1-expressing hepatoma cells

    PMID:15671032 PMID:16407187

    Open questions at the time
    • Molecular signals triggering endocytosis vs. recycling not defined
    • Motor/adaptor machinery for trafficking unknown
  5. 2008 High

    Identification of clathrin/AP2-dependent endocytosis as the specific internalization mechanism, and mapping of the ezetimibe binding site to extracellular loop C (Phe-532, Met-543), resolved how NPC1L1 enters cells and how ezetimibe blocks this process at a molecular level.

    Evidence Live-cell imaging, dominant-negative clathrin/AP2 constructs, chimeric NPC1L1 proteins, and point mutagenesis with radioligand binding

    PMID:18522832 PMID:18682566

    Open questions at the time
    • Cytoplasmic endocytic motif on NPC1L1 not identified
    • Adaptor protein linking NPC1L1 to clathrin not known
  6. 2008 High

    Triple-knockout (NPC1L1/ABCG5/ABCG8) mice established that NPC1L1 is genetically epistatic to ABCG5/G8 for phytosterol entry, confirming NPC1L1 as the sole gateway for dietary plant sterols.

    Evidence Triple KO mice with plasma phytosterol measurements

    PMID:18796403

    Open questions at the time
    • Whether NPC1L1 NTD binds phytosterols directly was untested
  7. 2009 High

    Identification of the myosin Vb–Rab11a–Rab11-FIP2 complex as the recycling machinery that returns NPC1L1 from the endocytic recycling compartment to the plasma membrane completed the outward arm of the trafficking cycle, alongside topology mapping revealing 13 transmembrane helices.

    Evidence Dominant-negative mutants of myosin Vb/Rab11a/Rab11-FIP2, microfilament disruption, protease protection topology assays

    PMID:19325169 PMID:19542231

    Open questions at the time
    • Whether Cdc42 participates in recycling not yet tested
    • How cholesterol sensing couples to recycling machinery unknown
  8. 2011 High

    Demonstration that the NTD directly binds cholesterol (but not plant sterols) via Leu-216 and that Cdc42 governs NPC1L1 recycling via N-WASP/Arp3 connected cholesterol sensing at the NTD to cytoplasmic trafficking machinery.

    Evidence NTD cholesterol binding assays with L216 mutagenesis, Cdc42 Co-IP and dominant-negative/constitutively active mutants, liver-specific Cdc42 KO mice

    PMID:21602275 PMID:21844200

    Open questions at the time
    • How NTD cholesterol binding transmits signal to cytoplasmic tail not resolved
    • Structural basis of NTD-cholesterol interaction unknown
  9. 2013 High

    Discovery that cholesterol binding releases the C-terminal YVNXXF motif to recruit the clathrin adaptor Numb bridged NTD cholesterol sensing to clathrin-mediated endocytosis, completing the signaling chain from extracellular cholesterol to vesicle formation.

    Evidence Motif mutagenesis, Co-IP with Numb, intestine-specific Numb KO mice with cholesterol absorption measurements

    PMID:24336247

    Open questions at the time
    • Whether additional adaptors contribute
    • Structural basis of YVNXXF–Numb recognition not resolved
  10. 2015 High

    Establishing NPC1L1 as the intestinal vitamin K transporter expanded its substrate repertoire beyond sterols to fat-soluble vitamins, with clinical relevance for warfarin–ezetimibe interactions.

    Evidence NPC1L1-overexpressing cells, Npc1l1 KO mice, ezetimibe/warfarin co-administration in vivo, retrospective clinical data

    PMID:25696002

    Open questions at the time
    • Whether vitamin K binds the NTD like cholesterol not tested
    • Relative contribution vs. other VK uptake routes in humans unclear
  11. 2017 High

    Showing that α-tocopherol (vitamin E) competitively binds the NTD and triggers NPC1L1 endocytosis via the same ezetimibe-sensitive mechanism as cholesterol unified the transport model across multiple lipophilic substrates.

    Evidence Competitive NTD binding assays, ΔNTD construct, endocytosis assays with ezetimibe

    PMID:28315682

    Open questions at the time
    • Structural basis of NTD accommodating both cholesterol and tocopherol unknown
    • Full substrate scope of NPC1L1 not delineated
  12. 2018 High

    FGF19-SHP signaling was shown to repress NPC1L1 transcription postprandially by inhibiting SREBP2, revealing a physiological feedback loop linking bile acid signaling to cholesterol absorption control.

    Evidence SHP-KO and FGF15-KO mice, FGF19 injection, luciferase reporters, intestinal organoid cholesterol uptake

    PMID:30521806

    Open questions at the time
    • Whether FGF19-SHP also regulates NPC1L1 in human liver not tested
    • Integration with PPARα and HNF1α regulatory inputs not modeled
  13. 2020 High

    Cryo-EM structures of apo (open) and ezetimibe-bound (closed) NPC1L1 revealed that ezetimibe occludes an intramolecular cholesterol transport tunnel by rotating the NTD ~60°, fundamentally reshaping understanding of drug inhibition from endocytosis blockade to tunnel occlusion.

    Evidence Cryo-EM structural determination of apo and ezetimibe-bound states; engineered disulfide bonds confirming inter-domain dynamics are essential

    PMID:32410728 PMID:32596471

    Open questions at the time
    • Cholesterol-bound intermediate structure not captured
    • How tunnel exit delivers cholesterol to the membrane bilayer unclear
  14. 2021 High

    Structures of cholesterol-enriched NPC1L1 revealed that the sterol-sensing domain responds to cholesterol occupancy by forming a structural cluster that ezetimibe destroys, and that NPC1L1 functions as a homodimer whose disruption (W347 mutation) impairs cholesterol and vitamin E uptake.

    Evidence Cryo-EM in three states (apo, cholesterol-enriched, ezetimibe-bound); W347 mutagenesis with uptake assays

    PMID:34272236 PMID:34407950

    Open questions at the time
    • Functional role of dimerization beyond uptake efficiency not clear
    • Whether SSD cluster formation directly triggers endocytic signaling unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how cholesterol traverses the full intramolecular tunnel and exits into the membrane bilayer, how NTD cholesterol binding is mechanistically coupled to YVNXXF motif release and Numb recruitment at the cytoplasmic tail, and whether NPC1L1 transports additional lipophilic substrates beyond cholesterol, phytosterols, vitamin K, and vitamin E.
  • No structure of a cholesterol-transiting intermediate exists
  • Coupling between NTD binding and cytoplasmic tail conformational change lacks structural evidence
  • Full substrate scope undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0008289 lipid binding 2 GO:0038024 cargo receptor activity 2
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 3 GO:0005768 endosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-382551 Transport of small molecules 7 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1430728 Metabolism 4 R-HSA-8963743 Digestion and absorption 3
Partners
AP2A1CDC42CLTAMYO5BNUMBRAB11ARAB11FIP2

Evidence

Reading pass · 35 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 is abolished in NPC1L1 knockout mouse membranes, and binding affinities of ezetimibe analogs to recombinant NPC1L1 are virtually identical to those for native enterocyte membranes. Radioligand binding assay with labeled ezetimibe glucuronide on 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 (sitosterol); NPC1L1 null mice show substantially reduced intestinal uptake and are completely resistant to diet-induced hypercholesterolemia, demonstrating NPC1L1 is the key intestinal sterol transporter. NPC1L1 knockout mouse model with cholesterol/phytosterol absorption measurements, plasma lipoprotein profiling, and intestinal gene expression analysis The Journal of biological chemistry High 15173162
2005 NPC1L1 protein localizes to a subcellular vesicular compartment enriched in Rab5 in HepG2 cells; NPC1L1 null cells exhibit aberrant plasma membrane uptake and transport of cholesterol and sphingolipids, and deregulation of caveolin transport and localization. Immunofluorescence colocalization with Rab5, NPC1L1 knockout mouse-derived cell lines, lipid transport assays The Journal of biological chemistry Medium 15671032
2008 Cholesterol specifically promotes clathrin/AP2-mediated endocytosis of NPC1L1; blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization; ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles, thereby inhibiting cholesterol uptake. Live cell imaging, pharmacological inhibition of endocytosis, clathrin/AP2 dominant-negative constructs, cholesterol uptake assays in cultured cells Cell metabolism High 18522832
2005 Cholesterol depletion (with methyl-β-cyclodextrin) induces relocation of NPC1L1 from the transferrin-positive endocytic recycling compartment to the plasma membrane, with a corresponding increase in cellular cholesterol uptake that is dose-dependently inhibited by ezetimibe; this defines cholesterol-regulated endocytic recycling of NPC1L1 as a mechanism regulating cellular cholesterol uptake. Stable NPC1L1-expressing hepatoma cell line, immunofluorescence, methyl-β-cyclodextrin cholesterol depletion, ezetimibe inhibition assays The Journal of biological chemistry High 16407187
2008 Ezetimibe and its analogs bind to an extracellular loop C (loop C) of NPC1L1; chimeric and mutational studies identified Phe-532 and Met-543 in a 61-aa region of loop C as key determinants of high-affinity binding; the binding site is distinct from where cholesterol binds (N-terminal loop A), and ezetimibe binding prevents conformational changes required for cholesterol translocation. Proteomic identification, chimeric NPC1L1 constructs, point mutagenesis, radioligand binding assay with [(3)H]AS Proceedings of the National Academy of Sciences of the United States of America High 18682566
2011 The N-terminal domain (NTD) of NPC1L1 binds cholesterol; mutation of Leu-216 eliminates cholesterol binding, decreases formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in 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 NPC1L1 endocytosis. Cholesterol binding assays with NTD, site-directed mutagenesis (L216 mutation), adenovirus-mediated expression in mouse liver, membrane microdomain fractionation, cholesterol uptake assays The Journal of biological chemistry High 21602275
2013 Cholesterol binding to the NTD of NPC1L1 releases the cytoplasmic C-terminal YVNXXF motif from association with the plasma membrane, enabling binding of the clathrin adaptor Numb; Numb specifically recognizes this motif and recruits clathrin for NPC1L1 internalization; disrupting the NPC1L1-Numb interaction decreases cholesterol uptake; intestinal Numb ablation in mice significantly reduces dietary cholesterol absorption. Identification of YVNXXF endocytic motif, Co-IP, dominant-negative/knockdown experiments, intestine-specific Numb knockout mice, cholesterol absorption measurements Nature medicine High 24336247
2009 The myosin Vb·Rab11a·Rab11-FIP2 triple complex on microfilaments is required for transport of NPC1L1 from the endocytic recycling compartment to the plasma membrane; dominant-negative mutants of any component inhibit NPC1L1 export and decrease cellular cholesterol uptake. Pharmacological microfilament disruption, dominant-negative mutant expression of myosin Vb, Rab11a, Rab11-FIP2, NPC1L1 localization imaging, cholesterol uptake assays The Journal of biological chemistry High 19542231
2011 The small GTPase Cdc42 interacts with NPC1L1 in a cholesterol-depletion-dependent manner; constitutively active or dominant-negative Cdc42 inhibits NPC1L1 transport to the plasma membrane; knockdown of Cdc42 downstream effectors N-WASP or Arp3 produces similar effects; liver-specific Cdc42 knockout mice show failure of NPC1L1 to localize to bile canaliculi and impaired biliary cholesterol reabsorption. Co-IP, dominant-negative/constitutively active Cdc42 mutants, siRNA knockdown of N-WASP/Arp3, liver-specific Cdc42 KO mice, NPC1L1 localization imaging The Journal of biological chemistry High 21844200
2009 NPC1L1 membrane topology was determined: the protein contains 13 transmembrane helices with the NH2-terminus in the lumen and COOH-terminus in the cytosol; it has seven cytoplasmic loops, four small and three large luminal loops; the putative sterol-sensing domain is oriented in the same manner as in HMGCR, NPC1, and SCAP. Protease protection assay and immunofluorescence in selectively permeabilized cells expressing NPC1L1 Journal of lipid research High 19325169
2000 NPC1L1 was identified as a new gene sharing 42% identity with NPC1; it contains a conserved NPC1 domain, a putative sterol-sensing domain, and a sterol-regulatory element in its promoter; the protein is predicted to function in cholesterol transport at a different subcellular location than NPC1. EST database search, full-length cDNA cloning, genomic characterization (20 exons, chromosome 7p13), sequence analysis Genomics Medium 10783261
2005 Native rat NPC1L1 is a 145 kDa highly glycosylated membrane protein enriched in the brush border membrane of intestinal enterocytes; recombinant Flag-tagged NPC1L1 expressed in CHO cells shows cell surface expression consistent with its proposed role as an intestinal sterol transporter. Sequential detergent extraction of enterocytes, Western blot, CHO cell expression with Flag tag, cell surface expression analysis Biochimica et biophysica acta Medium 15777641
2006 NPC1L1 localizes to the apical membrane of human jejunal enterocytes and is also detected in lysosomes, endosomes, and mitochondria; NPC1L1 knockdown in Caco-2 cells reduces micellar free cholesterol uptake and alters HMG-CoA reductase activity and ACAT expression; SR-BI mRNA decreases in NPC1L1-deficient cells. Cell fractionation, immunocytochemistry in human jejunum, NPC1L1 siRNA knockdown, [14C]cholesterol uptake assay, RT-PCR, enzyme activity assays Journal of lipid research High 16829661
2007 NPC1L1 in hepatoma cells mediates unidirectional, free-cholesterol-specific, ezetimibe-sensitive uptake; it does not transport esterified cholesterol, beta-sitosterol, or promote cholesterol efflux; NPC1L1-dependent cholesterol uptake requires cell-surface localization, adequate intracellular K+, but not Ca2+, the cytoskeleton, PKA, PKC, or pertussis-toxin-sensitive G-proteins. McArdle-RH7777 hepatoma cells stably expressing NPC1L1, cholesterol/phytosterol uptake assays, pharmacological inhibitors, ezetimibe treatment The Biochemical journal High 17523925
2008 NPC1L1-EGFP traffics dynamically between the plasma membrane and the transferrin-positive endocytic recycling compartment (ERC); ~42% of NPC1L1 resides in the ERC at steady state; acute cholesterol depletion blocks NPC1L1 internalization and stimulates recycling to plasma membrane; NPC1L1-EGFP facilitates transport of fluorescent sterols from plasma membrane to ERC; insulin induces translocation of NPC1L1-containing vesicles from ERC to the cell membrane; in polarized hepatoma cells, NPC1L1 localizes almost exclusively to the canalicular membrane. Live-cell fluorescence time-lapse microscopy, FRAP, fluorescent sterol analogs, NPC1L1-EGFP expression in hepatoma cells, insulin stimulation Journal of lipid research High 18523240
2012 In mouse small intestinal enterocytes in vivo, dietary cholesterol induces internalization of NPC1L1 from the brush border to the subapical layer beneath the brush border, where it partially colocalizes with the endosome marker Rab11; ezetimibe blocks the internalization of both NPC1L1 and cholesterol, causing their retention at the plasma membrane. Immunofluorescence and immunohistochemistry in mouse small intestine, dietary cholesterol challenge, ezetimibe treatment Journal of lipid research High 22811412
2010 Non-synonymous NPC1L1 variants from cholesterol low absorbers show defects in cholesterol uptake categorized as partial or severe; severely dysfunctional variants are rapidly degraded via the ER-associated degradation (ERAD) pathway; partially dysfunctional variants show defects in cholesterol-regulated recycling, subcellular localization, glycosylation, or protein stability; the S881L variant fails to localize to the liver canalicular membrane in vivo. Expression of 19 NPC1L1 variants in cells, cholesterol uptake assays, glycosylation analysis, ERAD inhibitor experiments, adenovirus-mediated expression in mouse liver, in vivo biliary cholesterol reabsorption measurement The Journal of biological chemistry High 21189420
2020 Cryo-EM structures of NPC1L1 in apo (open) and ezetimibe-bound (closed) states reveal that in the apo form the NTD interacts loosely, leaving its central cavity accessible for cholesterol loading; ezetimibe binding causes the NTD to rotate ~60°, creating a continuous tunnel enabling cholesterol movement into the plasma membrane; ezetimibe blocks transport by occluding this tunnel rather than competing with cholesterol binding. Cryo-electron microscopy structural 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 stable structural cluster formation in the SSD; ezetimibe binding deforms the SSD and destroys this structural cluster, inhibiting NPC1L1 function. Cryo-electron microscopy of human NPC1L1 in three states Science advances High 34272236
2021 Human NPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues in transmembrane helix 2 in a horizontal membrane orientation; mutation of Trp-347 disrupts dimerization and the resulting monomeric NPC1L1 shows reduced efficiency of cholesterol uptake; the same intramolecular channel mediates transport of both vitamin E and cholesterol. Cryo-EM structural determination, mutagenesis of dimerization interface (W347 mutation), cholesterol and vitamin E uptake functional assays Science advances High 34407950
2020 Constraining inter-domain dynamics of NPC1L1 by introducing single disulfide bonds abolishes cholesterol transport activity; the ezetimibe binding site resides at the interface between NPC1L1's three extracellular domains, consistent with ezetimibe blocking transport by binding to multiple domains simultaneously rather than a single loop. Engineered disulfide bonds in NPC1L1 and NPC1, lysosomal cholesterol efflux assay, ezetimibe binding analysis eLife High 32410728
2015 NPC1L1 mediates intestinal vitamin K (VK) absorption; NPC1L1-overexpressing intestinal cells show increased VK uptake; Npc1l1 knockout mice have reduced intestinal VK absorption; ezetimibe (an NPC1L1 inhibitor) reduces hepatic VK levels when co-administered with warfarin, enhancing its anticoagulant effect. NPC1L1 overexpression in intestinal cells (in vitro VK uptake), Npc1l1 knockout mice (in vivo VK absorption), ezetimibe/warfarin co-administration pharmacology in mice and retrospective clinical data Science translational medicine High 25696002
2017 NPC1L1 mediates α-tocopherol (vitamin E) absorption via the same mechanism as cholesterol: α-tocopherol competitively binds NPC1L1's N-terminal domain (NTD) with cholesterol; α-tocopherol treatment promotes NPC1L1 endocytosis; NPC1L1 lacking the NTD (NPC1L1ΔNTD) cannot respond to α-tocopherol; ezetimibe blocks α-tocopherol-induced NPC1L1 endocytosis. NPC1L1-GFP stable cell lines, competitive binding assays of α-tocopherol vs cholesterol on NTD, NPC1L1ΔNTD construct, endocytosis assays, ezetimibe inhibition Biochemical and biophysical research communications High 28315682
2008 NPC1L1 is genetically essential for phytosterols to enter the body; in mice lacking both ABCG5/G8 and NPC1L1 (triple knockout), phytosterol accumulation is prevented despite the absence of ABCG5/G8-mediated efflux, demonstrating NPC1L1 is the entry point for phytosterols. Triple knockout mouse model (NPC1L1/ABCG5/ABCG8), plasma phytosterol and cholesterol measurements, fecal sterol excretion analysis Journal of lipid research High 18796403
2008 SR-B1 does not contribute to intestinal cholesterol absorption mediated by NPC1L1: in NPC1L1/SR-B1 double null mice, intestinal cholesterol absorption was not different from NPC1L1 null alone, establishing NPC1L1 as the critical intestinal sterol transporter independent of SR-B1. NPC1L1/SR-B1 double knockout mice, intestinal cholesterol absorption measurements Atherosclerosis. Supplements High 18585981
2007 SREBP2 is responsible for cholesterol-dependent transcriptional regulation of NPC1L1; HNF4α plays a crucial role in the expression and cholesterol-dependent regulation of human NPC1L1, with binding sites identified at -209 to -197 and -52 to -40 in the NPC1L1 promoter; HNF4α knockdown reduces NPC1L1 expression and its response to cholesterol. Reporter gene (luciferase) assays with NPC1L1 promoter deletion/mutation constructs, EMSA, HNF4α siRNA knockdown Pharmaceutical research High 18080173
2010 HNF1α and SREBP2 are important regulators of NPC1L1 in human liver; SREBP2 dose-dependently activates the NPC1L1 promoter and its binding was confirmed by ChIP assay; HNF1α (not HNF4α) increases NPC1L1 promoter activity and gene expression, with an HNF1 binding site identified in the human NPC1L1 promoter confirmed by ChIP. Reporter gene assays, ChIP assay for SREBP2 and HNF1α binding to NPC1L1 promoter in vivo, gene expression correlation in human liver biopsies Journal of lipid research High 20460578
2010 PPARα positively regulates human NPC1L1 transcription via direct binding to a PPRE at -846/-834 upstream of the gene; PGC1α further stimulates SREBP2/HNF4α- and PPARα/RXRα-mediated NPC1L1 promoter activation; PPARα-specific knockdown decreases endogenous NPC1L1 mRNA and protein in HepG2 cells. Reporter gene assays, EMSA with PPARα/RXRα on PPRE, siPPARα knockdown, promoter deletion/mutation constructs Pharmaceutical research High 20953676
2018 Postprandial FGF19 signaling activates SHP (NR0B2), which inhibits SREBP2 activity through FGF19-induced phosphorylation of SHP; this leads to repression of intestinal NPC1L1 expression and decreased cholesterol absorption; SHP-knockout mice show increased NPC1L1 expression and cholesterol absorption that is not repressed by refeeding or FGF19. SHP-knockout mice, FGF15-knockout mice, FGF19 injection, RNA-seq, luciferase reporter assays, intestinal organoid cholesterol uptake assays, phosphorylation analysis Gastroenterology High 30521806
2018 Ganglioside GM3 and its synthesizing enzyme GM3 synthase (GM3S) are required for NPC1L1-dependent cholesterol uptake in cell models and in vivo; GM3S deficiency impairs NPC1L1-mediated cholesterol uptake and confers resistance to hypercholesterolemia in mice fed a high-cholesterol diet. GM3S-deficient cell lines, apoE-deficient and wild-type mice with GM3S deficiency, cholesterol uptake assays, high-cholesterol diet challenge Journal of lipid research High 30242108
2016 Ezetimibe-sensitive cholesterol uptake by NPC1L1 does not require endocytosis of NPC1L1; cell surface biotinylation shows ezetimibe does not alter NPC1L1-GFP endocytosis rate; two small-molecule inhibitors of general endocytosis fail to inhibit ezetimibe-sensitive [3H]cholesterol uptake from taurocholate micelles. Cell surface biotinylation, pharmacological endocytosis inhibitors, [3H]cholesterol uptake assay in rat hepatocytes expressing NPC1L1-GFP Molecular biology of the cell Medium 27075173
2014 Intestinal NPC1L1 expression alone (with no non-intestinal NPC1L1) is sufficient to drive increased cholesterol absorption, elevated blood/hepatic/biliary cholesterol, and increased VLDL/LDL atherogenic lipoprotein levels; cholesterol feeding induces formation of NPC1L1-positive vesicles beneath the intestinal brush border membrane in an ezetimibe-sensitive manner. Transgenic mouse model expressing human NPC1L1 only in gastrointestinal tract on NPC1L1/LDLR double-KO background; cholesterol absorption measurement, lipoprotein profiling, ezetimibe treatment, immunohistochemistry Atherosclerosis High 25463095
2022 NPC1L1 mediates uptake of vitamin E in drug-tolerant persister (DTP) cancer cells, partially preventing chemotherapy-triggered oxidative stress; NRF2 transcriptionally regulates NPC1L1 by binding to the -205 to -215 bp site on its promoter; decreased DNA methylation at this site also contributes to NPC1L1 upregulation. RNA-seq of MDR cancer cells, ChIP for NRF2 binding to NPC1L1 promoter, ezetimibe treatment functional studies, methylation analysis EMBO molecular medicine Medium 35023619
2009 In-vitro characterization of six NPC1L1 variants (D398G, T413M, R417W, G434R, A395V, G402S) from cholesterol low absorbers showed that four (D398G, T413M, R417W, G434R) reduce protein expression and alter subcellular localization; all four apically-expressed variants show reduced transport activity for both cholesterol and α-tocopherol in an ezetimibe-sensitive manner, indicating NPC1L1 transports both sterols via the same mechanism. Transient transfection in Caco-2 cells, stable overexpression of variants, [14C]cholesterol and α-tocopherol transport assays, immunofluorescence localization Pharmacogenetics and genomics Medium 19823104

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 576 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 535 15173162
2014 Inactivating mutations in NPC1L1 and protection from coronary heart disease. The New England journal of medicine 347 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 326 25770315
2008 The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell metabolism 283 18522832
2011 Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annual review of physiology 273 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 222 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 144 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 109 19272334
2005 Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment. Genomics 99 16297596
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
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 92 18682566
2011 The N-terminal domain of NPC1L1 protein binds cholesterol and plays essential roles in cholesterol uptake. The Journal of biological chemistry 91 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
2015 NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Science translational medicine 74 25696002
2015 Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease. European heart journal 74 25841872
2022 Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy. EMBO molecular medicine 73 35023619
2016 Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free radical biology & medicine 73 27634173
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 72 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
2018 Ezetimibe, a NPC1L1 inhibitor, attenuates neuronal apoptosis through AMPK dependent autophagy activation after MCAO in rats. Experimental neurology 64 29852178
2020 Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition. Science advances 63 32596471
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
2012 Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. Journal of lipid research 56 22811412
2006 NPC1L1: evolution from pharmacological target to physiological sterol transporter. Arteriosclerosis, thrombosis, and vascular biology 56 16973966
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
2021 Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake. Science advances 49 34272236
2008 Functional characterization of genetic variants in NPC1L1 supports the sequencing extremes strategy to identify complex trait genes. Human molecular genetics 49 18413323
2005 Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clinical genetics 49 15679830
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 39 35151363
2008 Ezetimibe blocks internalization of the NPC1L1/cholesterol complex. Cell metabolism 38 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
2010 Human NPC1L1 expression is positively regulated by PPARα. Pharmaceutical research 32 20953676
2016 Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases. Current medicinal chemistry 31 26923679
2013 Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol. Journal of lipid research 31 23482652
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
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
2020 Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins. eLife 29 32410728
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
2021 Lactobacillus mediates the expression of NPC1L1, CYP7A1, and ABCG5 genes to regulate cholesterol. Food science & nutrition 26 34925816
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
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 26 24773344
2008 Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and biophysical research communications 26 19071091
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
2021 Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption. Science advances 23 34407950
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
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 22 26335572
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
2019 Identification of hepatic NPC1L1 as an NAFLD risk factor evidenced by ezetimibe-mediated steatosis prevention and recovery. FASEB bioAdvances 21 32123832
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
2014 Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. Atherosclerosis 20 25463095
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
2018 NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains. Journal of lipid research 19 30242108
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
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 18 37307885
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
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 18 21181463
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
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 16 38103317
2022 The role of NPC1L1 in cancer. Frontiers in pharmacology 16 36034854
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
2007 Substituted oxazolidinones as novel NPC1L1 ligands for the inhibition of cholesterol absorption. Bioorganic & medicinal chemistry letters 15 18063367