Affinage

VLDLR

Very low-density lipoprotein receptor · UniProt P98155

Length
873 aa
Mass
96.1 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VLDLR is a multiligand lipoprotein receptor that serves as a core component of the Reelin signaling pathway, directly binding Reelin (with specificity conferred by the Reelin C-terminal region) and clusterin to trigger Dab1 tyrosine phosphorylation and downstream PI3K/Akt, Rap1/integrin, and Rac1/Yap cascades that govern neuronal migration, cortical lamination, dendrite development, and cardiomyocyte proliferation (PMID:12670700, PMID:14715136, PMID:24381170, PMID:28123028, PMID:38147128). VLDLR provides a cell-autonomous stop signal for migrating cortical neurons distinct from the migration-promoting role of ApoER2, and is required for positioning of mesencephalic dopaminergic neurons and suppression of retinal angiogenesis (PMID:17913789, PMID:32540847, PMID:23976984, PMID:21757581). Cell-surface VLDLR levels are tightly regulated by PCSK9-mediated lysosomal degradation, IDOL/LXR-induced ubiquitination of its cytoplasmic tail, SEL1L-dependent ER-associated degradation of misfolded mutants, and transcriptional control by HIF-1α under hypoxia and PPARα agonists (PMID:18039658, PMID:20427281, PMID:29371607, PMID:21970364, PMID:24899625). In the periphery VLDLR mediates VLDL lipid uptake driving brown adipocyte thermogenesis and macrophage ceramide-dependent inflammation, serves as a fibrin receptor supporting leukocyte transmigration, and functions as the entry receptor for encephalitic alphaviruses (SFV, EEEV) and HCV through engagement of its LDLR class A repeats with viral glycoproteins, as defined by cryo-EM structures (PMID:36516764, PMID:29057873, PMID:34929721, PMID:37098345, PMID:38176410, PMID:26699506).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2003 High

    Establishing that Reelin directly binds VLDLR and ApoER2 to induce Dab1 phosphorylation resolved the identity of the obligate neuronal Reelin receptors and showed no other receptor can substitute.

    Evidence Purified Reelin binding assays and Dab1 phosphorylation in cortical neurons from single/double receptor knockout mice

    PMID:12670700

    Open questions at the time
    • Structural basis of Reelin–VLDLR interaction not yet defined
    • Relative affinity contributions of each receptor unclear
    • Downstream signaling cascades beyond Dab1 not mapped
  2. 2004 High

    Demonstrating that Reelin promotes dendrite development through VLDLR/ApoER2–Dab1 extended the pathway's role beyond migration to post-migratory neuronal maturation.

    Evidence Pharmacological receptor blockade, Dab1 phosphorylation inhibitors, and recombinant Reelin rescue in hippocampal cultures and reeler mice

    PMID:14715136

    Open questions at the time
    • Which downstream effectors of Dab1 mediate dendrite outgrowth specifically
    • Whether VLDLR and ApoER2 contribute equally to this phenotype
  3. 2007 High

    Genetic epistasis revealed that VLDLR specifically provides a stop signal for migrating neurons (preventing marginal zone invasion), while ApoER2 is needed for late-born neuron migration — establishing non-redundant receptor functions in cortical lamination.

    Evidence BrdU fate mapping and layer-specific markers in Vldlr−/−, ApoER2−/−, and double knockout mice; Pafah1b complex interaction mapped to VLDLR NPxYL motif with compound mutant epistasis

    PMID:17330141 PMID:17913789

    Open questions at the time
    • Molecular basis distinguishing VLDLR stop signal from ApoER2 migration signal
    • Whether Pafah1b complex is sufficient for the VLDLR-specific stop signal
  4. 2007 High

    Discovery that PCSK9 degrades VLDLR through a catalytic-activity-independent mechanism identified the first post-translational pathway controlling VLDLR surface levels.

    Evidence Co-expression, secreted PCSK9 re-internalization, catalytic-dead mutant, and membrane-bound chimeras targeting VLDLR to lysosomes

    PMID:18039658

    Open questions at the time
    • Which VLDLR extracellular domain contacts PCSK9
    • In vivo tissue-specific consequences beyond adipocytes not yet tested
  5. 2010 High

    Identification of IDOL as an LXR-induced E3 ligase that ubiquitinates the VLDLR cytoplasmic tail established a second, transcription-coupled degradation axis and showed it attenuates Reelin–Dab1 signaling.

    Evidence Ubiquitination assays, LXR agonist treatment in vivo, Reelin binding and Dab1 phosphorylation readouts

    PMID:20427281

    Open questions at the time
    • Specific lysine residues ubiquitinated on VLDLR tail not mapped
    • Relative contribution of IDOL vs PCSK9 in different tissues
  6. 2011 High

    Multiple studies expanded VLDLR biology beyond Reelin: circulating PCSK9 regulates adipocyte VLDLR in vivo; VLDLR serves as a fibrin receptor for leukocyte transmigration; and a disease-causing VLDLR truncation mutation abolishes plasma membrane localization and retinal antiangiogenic function.

    Evidence Liver-specific PCSK9 manipulation in Pcsk9−/−/Ldlr−/− mice; SPR binding and transmigration assays in VLDLR-deficient mice; linkage/allelic complementation in Vldlr−/− mice with immunofluorescence of mutant protein

    PMID:21273557 PMID:21757581 PMID:22096238

    Open questions at the time
    • Fibrin β-domain binding site on VLDLR not structurally resolved
    • Whether antiangiogenic signaling uses Dab1 or a distinct pathway
  7. 2012 High

    HIF-1α was shown to directly activate VLDLR transcription through a functional HRE, explaining hypoxia-induced lipid accumulation and later providing the basis for hypoxia-dependent viral receptor expression.

    Evidence ChIP, dual-luciferase HRE reporter, HIF1A/VLDLR siRNA, lipid uptake under hypoxia

    PMID:21970364

    Open questions at the time
    • Whether HIF-1α–VLDLR axis operates in brain under physiological hypoxia
    • Interaction with other VLDLR transcriptional regulators (PPARs) under combined stimuli
  8. 2012 High

    FE65 was identified as a cytoplasmic adaptor linking VLDLR to APP via its PTB1 domain, modulating VLDLR surface levels and shedding, thus connecting Reelin receptor trafficking to amyloid precursor protein processing.

    Evidence Reciprocal co-IP in COS7 cells and brain lysates, cell-surface biotinylation, domain mapping, proteasome inhibitor studies

    PMID:22429478

    Open questions at the time
    • Physiological relevance of FE65-mediated VLDLR–APP linkage in neurodegeneration not tested in vivo
    • Whether FE65 competes with Dab1 for NPxY binding
  9. 2014 High

    PPARα was shown to directly transactivate the VLDLR promoter, and hepatic VLDLR induction proved essential for the triglyceride-lowering effect of fenofibrate, establishing VLDLR as a pharmacologically relevant lipid-clearance receptor in the liver.

    Evidence PPRE-reporter assays, fenofibrate treatment of Vldlr−/− and Pparα−/− mice, adenoviral VLDLR rescue

    PMID:24899625

    Open questions at the time
    • Whether hepatic VLDLR induction contributes to fenofibrate-associated hepatic steatosis
    • Relative roles of VLDLR vs LDLR in hepatic remnant clearance
  10. 2017 High

    The Reelin C-terminal region was shown to confer receptor-binding specificity for VLDLR over ApoER2, and VLDLR-dependent VLDL uptake in adipose macrophages was found to drive ceramide-mediated inflammatory polarization, linking VLDLR to metabolic inflammation.

    Evidence RELN-binding assays with CTR truncation, genetic epistasis in compound mutant mice; VLDLR KO bone marrow transplant, ceramide measurements, macrophage polarization

    PMID:28123028 PMID:29057873

    Open questions at the time
    • Structural determinant of Reelin CTR–VLDLR specificity not resolved
    • Whether ceramide signaling feeds back to regulate VLDLR expression
  11. 2018 High

    Disease-causing VLDLR missense mutations were shown to cause ER retention, calnexin association, and SEL1L-dependent proteasomal degradation, defining the proteostatic fate of pathogenic VLDLR variants.

    Evidence Co-IP with calnexin, ubiquitination assays, CRISPR SEL1L knockout delaying mutant and WT VLDLR degradation

    PMID:29371607

    Open questions at the time
    • Whether ER stress from accumulated mutant VLDLR contributes to cerebellar pathology
    • Proteostatic handling of VLDLR in neurons vs non-neuronal cells
  12. 2019 High

    Neuronal IDOL was found to control energy balance primarily through VLDLR (not LDLR) degradation, establishing VLDLR as a metabolically active receptor in hypothalamic neurons.

    Evidence Neuron-specific IDOL knockout mice, scRNA-seq of hypothalamus, metabolic phenotyping

    PMID:32072135

    Open questions at the time
    • What ligand(s) VLDLR transduces in hypothalamic energy sensing
    • Whether neuronal VLDLR signals through Dab1 or alternative pathways in this context
  13. 2020 High

    Rescue experiments in Vldlr-mutant cortex showed that VLDLR's stop-migration signal is cell-autonomous and mediated by Rap1/integrin/Akt, distinguishing it from Reelin-induced neuronal aggregation which does not require VLDLR.

    Evidence In utero electroporation rescue in Vldlr mutants, ectopic Reelin overexpression, Rap1/integrin/Akt pathway dissection

    PMID:32540847

    Open questions at the time
    • How Rap1 activation is mechanistically linked to Dab1 phosphorylation downstream of VLDLR
    • Whether the same pathway operates in non-cortical neurons
  14. 2021 High

    VLDLR was identified as the entry receptor for multiple encephalitic alphaviruses (SFV, EEEV, Sindbis), with viral E2–E1 engaging the VLDLR ligand-binding domain — a finding exploited to block infection in vivo with LBD-Fc decoys.

    Evidence Ectopic expression, VLP internalization, LBD-Fc competition and in vivo neonatal mouse protection, invertebrate orthologue functional assays

    PMID:34929721

    Open questions at the time
    • Atomic details of virus–receptor interaction not yet resolved
    • Whether VLDLR mediates viral entry in all susceptible cell types
  15. 2022 High

    VLDLR-mediated VLDL uptake in brown adipocytes was shown to fuel mitochondrial oxidation via lysosomal lipid processing and to activate PPARβ/δ-driven thermogenic gene expression, establishing VLDLR as a metabolic sensor in thermogenesis.

    Evidence Vldlr KO mice with cold exposure, lysosomal inhibitors, brown-adipocyte-specific PPARβ/δ KO

    PMID:36516764

    Open questions at the time
    • Identity of specific lipid species activating PPARβ/δ downstream of VLDLR-mediated uptake
    • Contribution of VLDLR vs other lipoprotein receptors in BAT under thermoneutral conditions
  16. 2023 High

    Cryo-EM structures of SFV–VLDLR revealed that multiple LA repeats (especially LA3) engage E1-DIII through salt bridges, with consecutive repeats rotating to enable multivalent binding — providing the first atomic-level view of VLDLR's virus-receptor interface and explaining its broad alphavirus tropism.

    Evidence Cryo-EM structure, individual LA repeat binding affinity measurements, mutagenesis

    PMID:37098345

    Open questions at the time
    • How pH-dependent conformational changes in endosomes release virus from VLDLR
    • Whether LA repeat engagement differs for physiological ligands like Reelin
  17. 2023 High

    In cardiomyocytes, VLDLR integrates opposing proliferative signals — Reelin promotes and thrombospondin-1 inhibits proliferation — through a Rac1/Yap axis, and cardiac-specific Vldlr deletion is cardioprotective after infarction.

    Evidence Cardiac-specific Vldlr KO, Reln mutant and Thbs1 cardiac deletion mice, cardiomyocyte cell cycle and Rac1/Yap signaling assays, apical resection model

    PMID:38147128

    Open questions at the time
    • How TSP-1 and Reelin compete or cooperate at the VLDLR ectodomain
    • Whether Dab1 is involved in cardiomyocyte VLDLR signaling
  18. 2024 High

    Cryo-EM structures of EEEV–VLDLR defined three distinct binding sites and showed that no single LA domain is necessary, enabling design of minimal decoy receptors that neutralize EEEV in vivo; the W132G human SNP was found to enhance EEEV attachment by switching binding modes.

    Evidence Multiple cryo-EM structures, mutagenesis, infection assays, in vivo decoy protection, W132G variant binding and attachment assays

    PMID:38176410 PMID:39127734

    Open questions at the time
    • Population-level significance of W132G for EEEV susceptibility
    • Whether decoy receptors based on VLDLR can achieve therapeutic neutralization against diverse alphaviruses
  19. 2024 High

    SFV neuroinvasion was shown to be strictly VLDLR-dependent, occurring specifically through infection of choroid plexus epithelial cells at the blood-CSF barrier, which express high VLDLR levels.

    Evidence VLDLR-deficient mice with intravenous SFV challenge, tissue-specific expression analysis, histological route-of-entry characterization

    PMID:39715740

    Open questions at the time
    • Whether other neurotropic viruses exploit VLDLR at the choroid plexus
    • Cell-type-specific VLDLR regulation in choroid plexus epithelium

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the structural basis of Reelin–VLDLR binding and how it differs from viral glycoprotein engagement; (2) how VLDLR signaling is decoded differently across cell types (neurons, cardiomyocytes, macrophages, brown adipocytes); (3) the precise mechanism by which VLDLR integrates opposing ligand signals (Reelin vs TSP-1) through shared downstream effectors.
  • No Reelin–VLDLR co-structure available
  • Cell-type-specific adaptor usage not systematically compared
  • In vivo relevance of multiple VLDLR splice variants incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 5 GO:0038024 cargo receptor activity 5 GO:0060089 molecular transducer activity 4 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
APOER2CLUDAB1FE65IDOLPCSK9RELNSEL1L

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Purified Reelin directly binds to VLDLR (and ApoER2), and this binding induces tyrosine phosphorylation of the cytoplasmic adaptor protein Disabled-1 (Dab1). Neurons lacking both ApoER2 and VLDLR show a complete absence of Reelin-induced Dab1 phosphorylation, demonstrating that no other receptor can compensate for their role. Purified Reelin binding assays, cortical neuron cultures from single and double receptor knockout mice, Dab1 phosphorylation assays, layer-specific marker fate mapping Brain research. Molecular brain research High 12670700
2004 Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2–Dab1 signaling pathway; addition of Reelin receptor antagonists or Dab1 phosphorylation inhibitors prevents dendrite outgrowth, and recombinant Reelin rescues the deficit in reeler cultures. In vivo analysis of reeler and receptor-mutant mice, dissociated hippocampal cultures, Reelin-blocking antibodies, receptor antagonists, Dab1 phosphorylation inhibitors, recombinant Reelin rescue Neuron High 14715136
2007 PCSK9 induces degradation of VLDLR (as well as LDLR and ApoER2). Wild-type PCSK9 and its gain-of-function mutant D374Y degrade VLDLR either through co-expression or re-internalization of secreted PCSK9; this degradation does not require PCSK9 catalytic activity and is enhanced by membrane-bound PCSK9 chimeras that target the receptor to late endosomes/lysosomes. Cellular co-expression, secreted PCSK9 re-internalization, membrane-bound PCSK9 chimeras, catalytic-dead mutant analysis, subcellular localization by immunofluorescence The Journal of biological chemistry High 18039658
2010 The E3 ubiquitin ligase IDOL ubiquitinates the cytoplasmic tail of VLDLR, leading to its degradation. IDOL expression is induced by liver X receptor (LXR) activation, and pharmacological LXR activation in mice increases IDOL expression and decreases Vldlr levels in vivo. IDOL-mediated VLDLR degradation reduces Reelin binding to VLDLR and decreases Dab1 phosphorylation. Ubiquitination assays, LXR agonist treatment in vivo and in vitro, Reelin binding assay, Dab1 phosphorylation assay, Western blotting The Journal of biological chemistry High 20427281
2007 Vldlr mediates a stop signal for migrating cortical neurons, whereas ApoER2 is essential for migration of late-generated neocortical neurons; fate mapping in single and double receptor knockout mice revealed divergent roles for the two Reelin receptors in radial neuronal migration. BrdU fate mapping, layer-specific markers in single and double receptor knockout mice Development (Cambridge, England) High 17913789
2011 Circulating PCSK9 originating from the liver regulates VLDLR protein levels on the surface of visceral adipocytes in vivo; liver-specific PCSK9 expression or inactivation modulates perigonadal VLDLR levels independently of LDLR. Immunohistochemistry in Pcsk9−/− mice, Pcsk9−/−Ldlr−/− mice, liver-specific PCSK9 expression and inactivation, in vivo fatty acid uptake assays Arteriosclerosis, thrombosis, and vascular biology High 21273557
2007 The Pafah1b complex catalytic subunits Pafah1b2 and Pafah1b3 specifically bind to the NPxYL sequence of VLDLR (but not ApoER2), and genetic epistasis shows that compound Pafah1b1+/−;Apoer2−/− mice display a reeler-like forebrain phenotype while Pafah1b1+/−;Vldlr−/− double mutants do not, placing Pafah1b complex function downstream of VLDLR in cortical layer formation. Binding assays identifying NPxYL interaction, compound mouse genetic epistasis analysis, cortical layer phenotyping PloS one High 17330141
2012 HIF-1α directly activates VLDLR gene transcription under hypoxia through a functional hypoxia-response element (HRE) at +405 in exon 1 of VLDLR, leading to increased LDL and VLDL uptake and intracellular lipid accumulation; HIF-2α is not involved. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), HIF1A/VLDLR siRNA knockdown, lipid uptake assays under hypoxia The Biochemical journal High 21970364
2011 VLDLR on retinal endothelial cell and RPE surfaces mediates an antiangiogenic signal that prevents retinal endothelial cells from migrating into the photoreceptor layer; a missense mutation (c.2239C>T) causing C-terminal truncation abolishes plasma membrane localization of VLDLR, resulting in loss of this antiangiogenic function. Genome-wide linkage, DNA sequencing, allelic complementation test with Vldlr−/− mice, Western blot, transient transfection with wild-type and mutant Vldlr, immunofluorescence localization Investigative ophthalmology & visual science High 21757581
2013 Clusterin binds directly to VLDLR (and ApoER2) and is internalized by cells expressing either receptor; clusterin binding triggers a Reelin-like signal including phosphorylation of Dab1 and activation of PI3K/Akt and n-cofilin. Binding assays, internalization assays, Dab1 phosphorylation assay, PI3K/Akt activation assays, SVZ explant cultures with clusterin blocking The Journal of biological chemistry High 24381170
2011 VLDLR functions as a novel endothelial cell receptor for fibrin, interacting with fibrin through fibrin βN-domains with high affinity; this interaction is inhibited by receptor-associated protein (RAP). VLDLR-deficient mice fail to support fibrin-dependent leukocyte transmigration, demonstrating a role for VLDLR in fibrin-dependent inflammation. ELISA, surface plasmon resonance, transendothelial migration assays with RAP inhibitor, VLDLR-deficient mouse in vivo transmigration assays Blood High 22096238
2015 VLDLR mediates hepatitis C virus (HCV) entry into hepatocytes independently of CD81; hypoxia-induced VLDLR expression confers HCV susceptibility to CD81-deficient cells, and ectopic VLDLR expression is sufficient for HCV entry. Hypoxic cell culture, CD81-deficient cell transduction with VLDLR, HCV infectivity assays, knockdown of known HCV entry factors Proceedings of the National Academy of Sciences of the United States of America High 26699506
2021 VLDLR (and ApoER2) acts as an entry receptor for alphaviruses including Semliki Forest virus (SFV), eastern equine encephalitis virus (EEEV), and Sindbis virus; the E2–E1 glycoproteins interact with the ligand-binding domains (LBDs) of VLDLR, and a VLDLR LBD-Fc fusion protein blocks infection and protects neonatal mice against lethal SFV challenge. Invertebrate VLDLR orthologues from mosquitoes and worms also function as alphavirus receptors. Ectopic expression assays, virus-like particle internalization, VLDLR LBD-Fc fusion protein competition/protection assays, in vivo mouse challenge model, invertebrate ortholog expression Nature High 34929721
2023 Cryo-EM structure of SFV in complex with VLDLR shows that VLDLR binds multiple E1-DIII sites on the virion through its membrane-distal LDLR class A (LA) repeats; LA3 has the highest binding affinity (interacting through salt bridges over 378 Ų surface area), and consecutive LA repeats undergo rotation to enable synergistic binding at multiple sites simultaneously. Cryo-electron microscopy structure determination, binding affinity measurements for individual LA repeats, mutagenesis Cell High 37098345
2024 Cryo-EM structures of EEEV-VLDLR complexes show EEEV uses two distinct sites on E1/E2 (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously; no single LA domain is necessary or sufficient for efficient EEEV infection. A minimal VLDLR decoy receptor designed from these structures neutralizes EEEV and protects mice from lethal challenge. Multiple cryo-EM structures, mutagenesis of binding sites, functional infection assays, in vivo mouse protection assays with decoy receptor Cell High 38176410
2024 Cryo-EM structural studies of EEEV-VLDLR identify three distinct binding sites (A, B, C) on EEEV engaged by different VLDLR LA repeats; the W132G variant of VLDLR impairs LA3 binding, switches binding modes, and significantly enhances EEEV cell attachment, suggesting this human SNP could confer heightened EEEV susceptibility. Cryo-EM structure determination, biochemical binding studies, cell attachment assays with wild-type and W132G mutant VLDLR Nature communications High 39127734
2024 SFV neuroinvasion is strictly dependent on VLDLR; SFV primarily enters the CNS through the blood-cerebrospinal fluid (B-CSF) barrier by infecting choroid plexus epithelial cells, which express distinctly high levels of VLDLR. In vivo VLDLR-deficient mouse model, intravenous SFV administration, tissue-specific VLDLR expression analysis, histological characterization of infection route Nature communications High 39715740
2012 FE65 interacts with VLDLR via its PTB1 domain (shown by GST pull-down and co-immunoprecipitation in COS7 cells and brain lysates), increases cell-surface levels of VLDLR and shedding of soluble VLDLR, promotes proteasomal degradation of the VLDLR C-terminal fragment, and acts as a linker between VLDLR and APP, altering trafficking and processing of both proteins. GST pull-down, co-immunoprecipitation in cell lines and brain lysates, cell-surface biotinylation, FE65 co-transfection with domain mutants, proteasome inhibitor studies Molecular neurodegeneration High 22429478
2013 Syntaxin 5 (Stx5) interacts with the C-terminal domain of VLDLR and prevents its advanced Golgi maturation while enabling transport of ER-glycosylated VLDLR to the plasma membrane via a Golgi-bypass pathway; Stx5 overexpression significantly interferes with VLDLR reaching the trans-Golgi network. Co-immunoprecipitation, pull-down assays, BFA treatment, low-temperature trafficking experiments, Western blot for glycosylation state, plasma membrane localization assays Experimental cell research Medium 23701949
2017 VLDLR expression in adipose tissue macrophages promotes obesity-induced adipose tissue inflammation and glucose intolerance; VLDL treatment upregulates intracellular C16:0 ceramide levels in a VLDLR-dependent manner, potentiating pro-inflammatory M1-like macrophage polarization. Adoptive transfer of VLDLR knockout bone marrow to wild-type mice relieves adipose tissue inflammation and improves insulin resistance. VLDLR knockout mice, bone marrow adoptive transfer, ceramide measurement, macrophage polarization assays, glucose tolerance tests Nature communications High 29057873
2019 IDOL (E3 ubiquitin ligase) controls energy balance and diet-induced obesity through degradation of neuronal VLDLR rather than LDLR; loss of IDOL in neurons protects against diet-induced obesity, and VLDLR is identified as the primary IDOL substrate mediating this metabolic effect. Tissue-specific IDOL knockout mice, single-cell RNA sequencing of hypothalamus, Western blot for receptor levels, metabolic phenotyping Nature metabolism High 32072135
2017 RELN C-terminal region (CTR) confers receptor-binding specificity; CTR truncation significantly decreases RELN binding to VLDLR (but not ApoER2), as shown by direct RELN-binding assay, and cortical neurons in CTR-mutant mice overmigrate into the marginal zone (phenotype similar to Vldlr-null mice). Genetic epistasis confirms RelnCTRdel/Apoer2null mice resemble reeler while RelnCTRdel/Vldlrnull do not. In vitro RELN-binding assay with VLDLR and ApoER2, genetic epistasis with double-mutant mice, BrdU fate mapping, cortical phenotyping The Journal of neuroscience High 28123028
2020 VLDLR is not required for Reelin-induced neuronal aggregation but suppresses neuronal invasion into the marginal zone via a cell-autonomous mechanism; rescue experiments implicate Rap1, integrin, and Akt as downstream mediators of VLDLR's stop-migration signal. Vldlr-mutant mice, ectopic Reelin overexpression, in utero electroporation rescue experiments, Rap1/integrin/Akt pathway analysis Development (Cambridge, England) High 32540847
2014 Fenofibrate (a PPARα agonist) markedly upregulates hepatic VLDLR transcription through a PPAR response element in the VLDLR promoter, and this induction is essential for the triglyceride-lowering effect of fenofibrate; Vldlr−/− mice fail to show the TG reduction in response to fenofibrate or high-fat diet VLDLR overexpression rescues the phenotype. Fenofibrate treatment of hyperlipidemic and diabetic mice, Vldlr−/− mice and Pparα−/− mice, hepatic VLDLR overexpression via adenovirus, PPRE-luciferase reporter assay Journal of lipid research High 24899625
2011 miR-200c targets Vldlr (and its ligand Reelin) to reduce epithelial proliferation during submandibular gland branching morphogenesis; loss- and gain-of-function of miR-200c alter proliferation through a Vldlr-dependent FGFR signaling mechanism. miRNA loss- and gain-of-function in mouse submandibular gland organ culture, miR-200c target prediction and validation, FGFR signaling readout Development (Cambridge, England) Medium 22115756
2018 Disease-causing missense VLDLR mutants associated with Dysequilibrium syndrome are retained in the ER where they associate with calnexin, become ubiquitinated, and are degraded predominantly by the proteasomal pathway via interaction with the ER degradation adaptor SEL1L; SEL1L knockout (CRISPR/Cas9) delays degradation of both wild-type and mutant VLDLR. Co-immunoprecipitation with calnexin, ubiquitination assay with proteasome inhibitors, CRISPR/Cas9 SEL1L knockout, ER stress markers, protein aggregation assays Scientific reports High 29371607
2022 VLDLR-mediated VLDL uptake in brown adipocytes provides lipid fuels for mitochondrial oxidation via lysosomal processing and activates PPARβ/δ to drive thermogenic gene expression; VLDLR knockout mice show impaired cold-induced thermogenesis, and brown-adipocyte-specific PPARβ/δ knockout attenuates VLDL-induced thermogenic capacity. VLDLR knockout mice, cold exposure experiments, lysosomal inhibitors, PPARβ/δ adipocyte-specific knockout mice, thermogenic gene expression assays Cell reports High 36516764
2023 VLDLR acts as a receptor in cardiomyocytes consolidating opposing signals: thrombospondin-1 (TSP-1) inhibits cardiomyocyte proliferation through VLDLR via Rac1 and subsequent Yap phosphorylation/nuclear translocation, while Reelin (from cardiac Schwann cells and lymphatic endothelial cells) promotes proliferation through the same receptor. Cardiac-specific Vldlr deletion promotes cardiomyocyte proliferation and is cardioprotective after myocardial infarction. Receptor profiling in postnatal cardiomyocytes, cardiac-specific Vldlr knockout mice, Reln mutant mice, Thbs1 cardiac deletion, cardiomyocyte cell cycle assays, Rac1/Yap signaling assays, apical resection model Basic research in cardiology High 38147128
2009 The VLDLR-III splice variant (lacking the third complement-type repeat, exon 4) exhibits the highest capacity for binding apoE-containing beta-VLDL in vitro and is more effective than other variants in removing apoE-containing lipoproteins from circulation in vivo; this exon 4-skipping is neuron-specific and absent in primary astrocytes. In vitro lipoprotein binding assays, in vivo lipoprotein clearance assays, RT-PCR of VLDLR splice variants in human cerebellum and mouse brain regions, primary neuron and astrocyte cultures Brain research Medium 19393635
2013 ApoER2 and VLDLr are required for Reelin-mediated migration and final positioning of mesencephalic dopaminergic (mDA) neurons in the substantia nigra, VTA, and retrorubral field; VLDLr−/− mice show a more pronounced reduction and mispositioning of mDA neurons than ApoER2−/− mice, and ApoER2/VLDLr double knockouts phenocopy Reelin and Dab1 mutants. Single and double receptor knockout mice, immunohistochemistry for dopaminergic neuron markers, neuronal counting and positioning analysis PloS one High 23976984
2024 SIRT1 attenuates hepatic lipid accumulation by suppressing VLDLR protein levels; SIRT1 loss increases VLDLR in a HIF-1α-dependent manner (not ER stress-dependent), and SIRT1 activation prevents ER stress-induced increases in hepatic VLDLR. Sirt1−/− mice, fructose-fed rat model, Huh-7 cells with SIRT1 siRNA/pharmacological inhibition, HIF-1α inhibitor, tunicamycin ER stress model with SIRT1 activator Cell communication and signaling Medium 38807218
2014 A CRISPR-deleted intronic enhancer element spanning rs3780181 in VLDLR reduces VLDLR expression ~1.2-fold in HEK293T cells; the rs3780181-A risk allele (associated with increased TC/LDL-C) shows significantly less enhancer activity than the G allele, with differential binding to nuclear proteins including IRF2. CRISPR-Cas9 enhancer deletion, allele-specific luciferase reporter assay in HepG2/THP-1/SGBS cells, nuclear protein binding assay, eQTL analysis in liver Human molecular genetics Medium 30445632

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. The Journal of biological chemistry 394 18039658
2004 Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway. Neuron 313 14715136
2014 Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Molecular cancer research : MCR 250 24874432
2011 Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arteriosclerosis, thrombosis, and vascular biology 211 21273557
2006 Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Investigative ophthalmology & visual science 152 16384981
2007 Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development (Cambridge, England) 134 17913789
2010 The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. The Journal of biological chemistry 116 20427281
2011 Nanoceria inhibit the development and promote the regression of pathologic retinal neovascularization in the Vldlr knockout mouse. PloS one 109 21364932
2021 VLDLR and ApoER2 are receptors for multiple alphaviruses. Nature 105 34929721
2008 Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retinal angiomatous proliferation. Investigative ophthalmology & visual science 105 18172119
1994 Mouse very-low-density-lipoprotein receptor (VLDLR) cDNA cloning, tissue-specific expression and evolutionary relationship with the low-density-lipoprotein receptor. European journal of biochemistry 101 7925422
1996 Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer's disease. Journal of neuropathology and experimental neurology 100 8786409
2003 Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Brain research. Molecular brain research 88 12670700
2003 Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice. The Journal of comparative neurology 86 12687696
2013 Clusterin is a ligand for apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) and signals via the Reelin-signaling pathway. The Journal of biological chemistry 81 24381170
2008 Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proceedings of the National Academy of Sciences of the United States of America 79 18326629
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