Affinage

RBP4

Retinol-binding protein 4 · UniProt P02753

Length
201 aa
Mass
23.0 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBP4 is the principal hepatocyte-derived circulating retinol carrier, mobilizing vitamin A from hepatic storage pools into the bloodstream for delivery to peripheral tissues; loss of RBP4 traps retinol in the liver, abolishes serum retinol, and causes severe retinal degeneration and ocular developmental defects (PMID:26974396, PMID:27797907). Circulating RBP4 levels are sustained by its association with transthyretin (TTR), and disrupting this interaction — pharmacologically with the nonretinoid antagonist A1120 or by antisense knockdown of TTR — sharply lowers plasma RBP4 (PMID:23211825, PMID:25524914). Beyond retinol, the hydrophobic ligand pocket of RBP4 also accommodates fatty acids such as palmitate and laurate (PMID:29414511). Retinol delivery to cells is executed by two receptors: STRA6, a bidirectional retinol channel in extrahepatic tissues whose transfer activity is coupled to LRAT-driven retinyl ester formation, and RBPR2, a high-affinity hepatic/intestinal retinol transporter (PMID:18316031, PMID:23105095). Dominant-negative RBP4 mutations that lose retinol binding yet bind STRA6 more avidly block productive vitamin A delivery and cause human ocular birth defects, with maternal transmission acting through impaired placental retinol transfer (PMID:25910211, PMID:29847795). At elevated concentrations RBP4 functions as a pro-inflammatory adipokine/hepatokine: it activates adipose antigen-presenting cells through MyD88-dependent MAPK (JNK/ERK/p38) and NF-κB signaling, drives CD4 Th1 polarization and adipose inflammation sufficient to induce insulin resistance, and stimulates lipolysis via a TNFα-mediated paracrine loop (PMID:24606904, PMID:26936962, PMID:32167208). Through STRA6, RBP4 transduces JAK2/STAT3 signaling that promotes colon cancer stem cell maintenance and denervation-induced skeletal muscle atrophy, while apo-RBP4 prolongs the RBP4–STRA6 interaction to activate STAT5/SOCS3 and impair insulin signaling (PMID:28689994, PMID:39031684, PMID:28528355). Hepatic RBP4 expression oscillates under circadian BMAL1→DBP control to gate insulin sensitivity by time of day, and is regulated by HMGA1/cAMP and suppressed by IL-1β via IL-1R/NF-κB in adipocytes (PMID:26564180, PMID:19460132, PMID:23460908). Notably, modestly elevated liver-secreted RBP4 alone does not impair glucose homeostasis, indicating that its metabolic pathogenicity depends on context such as adipose inflammation (PMID:30126844).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 Medium

    Established an early developmental role for Rbp4 beyond adult retinol transport, showing it is required in the zebrafish yolk syncytial layer for yolk extension and proper liver bud formation.

    Evidence Morpholino knockdown in zebrafish YSL with in situ hybridization and pathway inhibition (Nodal, Hedgehog, retinoic acid)

    PMID:17945029

    Open questions at the time
    • Mechanism linking Rbp4 to Fibronectin1 regulation not resolved
    • Relevance to mammalian liver/embryo development not established
  2. 2008 High

    Resolved how cells acquire retinol from circulating RBP4 by identifying STRA6 as a bidirectional retinol channel coupled to intracellular LRAT esterification.

    Evidence Cell-based retinol transfer assay in STRA6-expressing fibroblasts ± LRAT; zebrafish stra6/rbp4 loss-of-function with rescue

    PMID:18316031

    Open questions at the time
    • Structural basis of bidirectional transport not defined
    • Tissue-specific contributions of STRA6 vs other routes unquantified
  3. 2009 Medium

    Defined transcriptional control of RBP4 by cAMP-HMGA1 signaling and by an adipocyte promoter SNP, linking RBP4 expression levels to glucose homeostasis.

    Evidence Hmga1 knockout mice with glucagon/cAMP stimulation; luciferase promoter-reporter and EMSA in 3T3-L1 adipocytes

    PMID:19460132 PMID:19851303

    Open questions at the time
    • DNA-binding suppressive factor at the -803 SNP unidentified
    • Direct vs indirect HMGA1 action on the RBP4 promoter not distinguished
  4. 2012 High

    Identified a second RBP4 receptor, RBPR2, expanding retinol uptake beyond STRA6 to a high-affinity hepatic/intestinal route inversely tied to retinol stores.

    Evidence Heterologous expression with binding/transport assays, siRNA knockdown, and in vivo correlation with hepatic retinol

    PMID:23105095

    Open questions at the time
    • Whether RBPR2 channels retinol bidirectionally like STRA6 unknown
    • In vivo physiological requirement via genetic knockout not shown
  5. 2013 High

    Established that the RBP4-TTR interaction maintains circulating RBP4 and is druggable, and that inflammatory cytokines suppress RBP4 expression.

    Evidence A1120 antagonist in vitro binding and in vivo dosing in Abca4-/- mice; IL-1β/TNF-α/LPS treatment with IL-1R blockade and NF-κB inhibitors in human adipocytes

    PMID:23211825 PMID:23460908

    Open questions at the time
    • Physiological trigger normally regulating TTR-RBP4 complex dynamics unclear
    • Net consequence of cytokine-driven RBP4 suppression in vivo not established
  6. 2014 High

    Demonstrated that RBP4 acts as an immune signal sufficient to cause insulin resistance, activating adipose antigen-presenting cells via JNK to drive Th1 polarization, and identified MAPK/ERK as the route for VSMC proliferation.

    Evidence RBP4-overexpressing mice with adoptive transfer of activated APCs and JNK inhibition; RBP4 treatment of rat aortic SMCs with ERK (PD98059) and JAK2 (AG490) inhibitors

    PMID:24606904 PMID:24888764

    Open questions at the time
    • Cell-surface receptor mediating APC activation not identified
    • Antigen specificity of induced T-cell response not defined
  7. 2015 High

    Resolved the upstream signaling for RBP4-induced inflammation and placed RBP4 downstream of the circadian clock as a hepatokine gating insulin sensitivity by time of day.

    Evidence MyD88-/- macrophages and pharmacological MAPK/NF-κB inhibition; CTLA4-Ig and RBP4-/- mice on high-fat diet; liver-specific Bmal1 KO with Dbp/Rbp4 knockdown and overexpression; human family genetics with mutant RBP4-STRA6 affinity measurements

    PMID:25910211 PMID:26564180 PMID:26936962

    Open questions at the time
    • How MyD88 is engaged by RBP4 (receptor/ligand) remains undefined
    • Mechanism by which dominant-negative mutants sequester STRA6 not structurally resolved
  8. 2016 High

    Established hepatocytes as the dominant source of circulating RBP4 and confirmed RBP4's essential role in hepatic retinol mobilization and retinal integrity.

    Evidence Hepatocyte-specific RBP4 knockout (LRKO) and global Rbp4 knockout mice with serum/liver retinol measurement and retinal histology/ERG

    PMID:26974396 PMID:27797907

    Open questions at the time
    • Contribution of intestinal/macrophage RBP4 to local signaling pools not quantified
    • Retinal phenotype mechanism downstream of retinol deficiency vs RBP4 signaling not separated
  9. 2017 Medium

    Showed that the retinol-loading state of RBP4 dictates STRA6 signaling output, with apo-RBP4 driving STAT5/SOCS3 insulin resistance and STRA6/JAK2/STAT3 promoting cancer stem cell maintenance.

    Evidence Co-IP distinguishing apo- vs holo-RBP4 binding to STRA6 in adipocytes with signaling readouts and in vivo rat injection; STRA6/RBP4 knockdown in colon cancer with sphere/tumor initiation and xenograft assays

    PMID:28528355 PMID:28689994

    Open questions at the time
    • Apo- vs holo-RBP4 signaling distinction rests on a single lab's Co-IP
    • Structural basis for differential STRA6 engagement by ligand state unresolved
  10. 2018 High

    Refined the metabolic model by showing modest liver RBP4 elevation alone is insufficient for glucose dysregulation, and revealed fatty acids as a second physiological ligand.

    Evidence AAV liver-specific RBP4 overexpression with clamp/GTT on high-fat diet; high-resolution crystal structures of RBP4 from plasma/urine/amniotic fluid with mass spectrometry; canine K12del pedigree secretion analysis

    PMID:29414511 PMID:29847795 PMID:30126844

    Open questions at the time
    • Functional consequence of fatty acid binding by RBP4 unknown
    • Context that converts elevated RBP4 into a pathogenic signal not pinpointed
  11. 2022 Medium

    Extended RBP4 pathology to NAFLD via an exosomal hepatocyte-Kupffer cell feedback loop and to vascular disease via JAK2/STAT3-driven VSMC proliferation.

    Evidence Exosome isolation with Kupffer cell co-culture, NOX2/NF-κB inhibition and in vivo RBP4 injection; RBP4 overexpression in VSMCs with vitamin D treatment and diabetic atherosclerosis rat model

    PMID:35082965 PMID:36572267

    Open questions at the time
    • Receptor mediating exosomal RBP4 uptake by Kupffer cells unidentified
    • Both rest on single-lab cell-culture-driven mechanisms
  12. 2024 High

    Demonstrated a STRA6/JAK2/STAT3-dependent role for holo-RBP4 in denervation-induced muscle atrophy, with genetic and pharmacological (A1120) protection.

    Evidence RBP4 knockout mice, holo/apo-RBP4 intramuscular injection, STRA6/JAK2/STAT3 siRNA and inhibitors, A1120, and C2C12 myotube assays

    PMID:39031684

    Open questions at the time
    • Source of RBP4 acting on denervated muscle (systemic vs local) not defined
    • Relationship between holo-RBP4 atrophy signaling and apo-RBP4 insulin resistance signaling unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular receptor and binding interface by which RBP4 activates immune cells (MyD88-dependent APC/macrophage responses) independent of STRA6 remain unidentified.
  • No receptor linking RBP4 to MyD88 engagement defined
  • Functional role of fatty-acid-bound RBP4 not established
  • Determinants converting elevated RBP4 into a pathogenic versus neutral signal unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0140104 molecular carrier activity 4 GO:0005215 transporter activity 2 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2
Partners
LRATRBPR2STRA6TTR
Complex memberships
RBP4-transthyretin (TTR) complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 STRA6 mediates bidirectional retinol transfer between RBP4 and cells; this transfer is enhanced by lecithin:retinol acyltransferase (LRAT) and is bidirectional, indicating STRA6 functions as a retinol channel/transporter. In zebrafish lacking Stra6, holo-Rbp4 causes nonspecific vitamin A excess in embryonic tissues, impairing retinoic acid receptor signaling; reducing Rbp4 levels alleviates these defects. Cell-based retinol transfer assay (NIH 3T3 fibroblasts expressing STRA6 ± LRAT); zebrafish loss-of-function (morpholino knockdown of stra6 and rbp4); pharmacological treatment Cell metabolism High 18316031
2012 RBPR2 (RBP4 receptor-2) is a novel retinol transporter expressed primarily in liver and intestine that confers high-affinity RBP4 binding and retinol transport when expressed in cultured cells; RBPR2 knockdown reduces RBP4 binding and retinol transport. RBPR2 expression is suppressed by retinol and retinoic acid and correlates inversely with liver retinol stores in vivo, identifying it as a hepatic receptor for circulating RBP4. Heterologous expression in cultured cells (binding and transport assays); siRNA knockdown; in vivo correlation of RBPR2 expression with retinol stores The Journal of biological chemistry High 23105095
2014 RBP4 directly activates adipose tissue antigen-presenting cells (APCs) through a JNK-dependent pathway, leading to CD4 T cell Th1 polarization and adipose tissue inflammation. Transfer of RBP4-activated APCs into normal mice is sufficient to induce adipose tissue inflammation, insulin resistance, and glucose intolerance. RBP4-overexpressing mouse model (RBP4-Ox); adoptive transfer of RBP4-activated APCs into normal mice; JNK pathway inhibition Cell metabolism High 24606904
2016 RBP4-induced macrophage antigen presentation and T-cell activation requires MyD88 signaling and downstream MAPK (JNK, ERK, p38) and NF-κB pathways. In macrophages from MyD88−/− mice, RBP4 fails to stimulate TNF, IL-12, and IL-6 secretion or CD4 T-cell activation. In vivo blockade of antigen presentation with CTLA4-Ig reduces adipose tissue inflammation and improves insulin resistance in RBP4-Ox mice. RBP4−/− mice on high-fat diet show reduced adipose tissue inflammation and improved insulin sensitivity. MyD88−/− macrophages; pharmacological inhibition of JNK/ERK/p38/NF-κB; CTLA4-Ig treatment in vivo; RBP4−/− knockout mice on high-fat diet Diabetes High 26936962
2015 Dominant-negative missense mutations in RBP4 greatly reduce retinol binding yet paradoxically increase RBP4 affinity for its cell-surface receptor STRA6. By occupying STRA6 nonproductively, these mutant proteins disrupt vitamin A delivery by wild-type RBP4 both within the fetus and, for maternally transmitted alleles, at the placenta, establishing a dominant-negative mechanism for ocular birth defects. Structural/biochemical analysis of mutant RBP4 retinol-binding and STRA6-binding affinities; genetic analysis of three human families with eye malformations; maternal transmission studies Cell High 25910211
2016 Hepatocytes are the principal source of circulating RBP4. Liver-specific RBP4 knockout mice have undetectable circulating RBP4 despite intact and inducible adipose tissue RBP4 expression and secretion, demonstrating that adipocyte-derived RBP4 does not significantly contribute to circulating levels even in diet-induced insulin resistance. Hepatocyte-specific Cre-mediated RBP4 deletion (LRKO mice); measurement of serum RBP4 and adipose RBP4 expression/secretion in lean and obese states Diabetes High 27797907
2018 Liver-specific overexpression of RBP4 via AAV to levels comparable to obesity-associated elevation does not impair glucose homeostasis in mice, even under high-fat diet challenge, indicating that modestly elevated liver-secreted circulating RBP4 is not itself causative for impaired glucose metabolism. Adeno-associated virus (AAV)-mediated liver-specific RBP4 overexpression; glucose tolerance tests; insulin clamp; high-fat diet challenge The Journal of biological chemistry High 30126844
2009 HMGA1 transcription factor is required for basal and cAMP-induced RBP4 gene and protein expression. In Hmga1-knockout mice, basal and glucagon-induced RBP4 expression is severely attenuated. This identifies a cAMP–HMGA1–RBP4 pathway regulating glucose homeostasis, where RBP4 reduction correlates inversely with increased GLUT4 and activated Akt in skeletal muscle and fat. Hmga1 knockout mouse model; glucagon administration; cAMP treatment of cells; mRNA and protein quantification of RBP4 and GLUT4/Akt BMC biology Medium 19460132
2015 Hepatic RBP4 expression oscillates diurnally under circadian control. BMAL1 regulates hepatic RBP4 via its direct target DBP. Hepatic knockdown of RBP4 or DBP improves whole-body insulin sensitivity in a time-of-day-dependent manner; hepatic overexpression of RBP4 reverses insulin-sensitizing effects of liver-specific BMAL1 depletion, placing RBP4 as a hepatokine downstream of the circadian clock regulating glucose metabolism. Liver-specific Bmal1 knockout mice; recombinant adenovirus-mediated shRNA knockdown of Dbp or Rbp4 in liver; hepatic RBP4 overexpression; insulin sensitivity tests at different times of day Diabetologia Medium 26564180
2014 Circulating transthyretin (TTR) is a critical determinant of plasma RBP4 levels. Antisense oligonucleotide-mediated knockdown of TTR decreases circulating TTR and RBP4 by 80–95%, improving insulin sensitivity in obese mice (increased glucose infusion rate, greater suppression of hepatic glucose production, increased muscle glucose uptake), demonstrating that TTR-RBP4 complex formation is required for maintaining elevated circulating RBP4. TTR antisense oligonucleotide (ASO) treatment in ob/ob and high-fat diet mice; hyperinsulinemic-euglycemic clamp; hepatic glucose production measurement; insulin signaling in muscle Diabetes High 25524914
2018 Human plasma RBP4, in addition to retinol, binds fatty acids (including palmitic and lauric acid) in its hydrophobic ligand-binding site. High-resolution crystal structures of human RBP4 from plasma, urine, and amniotic fluid all showed a fatty acid molecule bound in the retinol-binding pocket, confirmed by mass spectrometry. X-ray crystallography (high-resolution 3D structures of apo- and holo-RBP4 from plasma, urine, amniotic fluid); mass spectrometry confirmation of fatty acid binding Biochimica et biophysica acta. Molecular and cell biology of lipids High 29414511
2017 STRA6, activated by RBP4, transduces a JAK2-STAT3 signaling cascade that promotes cancer stem cell maintenance in colon cancer. Downregulation of STRA6 or RBP4 decreases cancer stem cell fraction and sphere/tumor initiation frequency. High-fat diet increases STRA6 levels and promotes tumor growth in a xenograft model; STRA6 downregulation delays tumor initiation and impairs stemness marker expression. STRA6/RBP4 siRNA knockdown in colon cancer cells; sphere formation and tumor initiation assays; xenograft mouse model; high-fat diet mouse model Stem cell reports Medium 28689994
2017 Retinol-free RBP4 (apo-RBP4), but not retinol-bound RBP4 (holo-RBP4), activates STRA6 signaling and induces insulin resistance. In vitro, apo-RBP4 prolongs RBP4–STRA6 interaction (shown by co-immunoprecipitation) and elevates JAK2/STAT5 cascade activation and SOCS3 expression, while decreasing IR/IRS1 phosphorylation and GLUT4 translocation. Exogenous apo-RBP4 injection into pregnant rats attenuates insulin sensitivity. Co-immunoprecipitation of RBP4 with STRA6 in human adipocytes treated with apo- vs. holo-RBP4; Western blotting of JAK2/STAT5/SOCS3/IR/IRS1; GLUT4 translocation by immunofluorescence; in vivo apo-RBP4 injection in pregnant rats Archives of gynecology and obstetrics Medium 28528355
2020 RBP4 directly stimulates basal lipolysis in human adipocytes in vitro. Additionally, conditioned media from RBP4-activated macrophages markedly increases basal lipolysis and impairs insulin-mediated lipolysis suppression; RBP4 treatment of macrophages increases TNFα production, indicating a paracrine mechanism linking RBP4-driven macrophage activation to adipocyte insulin resistance via pro-inflammatory cytokines. Direct RBP4 treatment of human adipocytes (in vitro lipolysis assay); conditioned media experiments from RBP4-activated macrophages applied to adipocytes; TNFα ELISA from macrophages FASEB journal Medium 32167208
2016 Rbp4-deficient mice (C57BL/6 background) accumulate retinol in the liver but have undetectable serum retinol, demonstrating that RBP4 is critical for mobilization of retinol from hepatic storage pools into circulation. Loss of RBP4 causes severe retinal structural abnormalities (loss of peripheral choroid, photoreceptor layer degeneration, reduced ganglion cells) and ocular developmental defects (retinal depigmentation, optic disc abnormality, persistent hyaloid artery). Rbp4 knockout mice (C57BL/6 background); electroretinography; retinal histology; retinol measurement in serum and liver Laboratory investigation High 26974396
2013 A1120, a nonretinoid RBP4 antagonist, inhibits the RBP4–transthyretin (TTR) interaction in vitro with superior potency compared to fenretinide, does not inhibit RPE65-mediated isomerohydrolase activity, and reduces serum RBP4 by 75% in mice; this reduction correlates with decreased visual cycle retinoids and reduced ocular lipofuscin bisretinoid accumulation in Abca4−/− mice, confirming that RBP4–TTR interaction maintains circulating RBP4 levels required for retinal retinoid delivery. In vitro RBP4 binding assay; RBP4-TTR interaction assay; RPE microsome isomerohydrolase assay; in vivo mouse dosing with A1120; biochemical and electrophysiological measurement of retinoids and lipofuscin Investigative ophthalmology & visual science High 23211825
2013 IL-1β downregulates RBP4 mRNA expression and secretion in human adipocytes in a time- and dose-dependent manner. This inhibitory effect is mediated via the IL-1 receptor and NF-κB, as blockade of IL-1 receptor or NF-κB inhibitors reverse the effect. TNF-α and LPS also inhibit RBP4 expression in macrophages, while IL-6 has no effect. IL-1β, TNF-α, LPS, IL-6 treatment of human SGBS and primary adipocytes; IL-1 receptor blocking antibody; NF-κB inhibitors (CAPE, SC-514); qPCR and ELISA for RBP4 PloS one Medium 23460908
2009 The minor allele (-803A) of the RBP4 promoter SNP increases RBP4 promoter activity 2–3 fold in 3T3-L1 adipocytes (shown by promoter-reporter assay), and this activity is further enhanced by 9-cis-retinoic acid and 8-Br-cAMP. EMSA showed that the -803G>A SNP modulates affinity for an unidentified DNA-binding suppressive factor, indicating that the minor allele relieves transcriptional repression to increase RBP4 adipocyte expression. Luciferase promoter activity assay in 3T3-L1 adipocytes; electrophoretic mobility shift assay (EMSA); allele-specific relative quantification of RBP4 transcripts in heterozygotes Obesity (Silver Spring, Md.) Medium 19851303
2022 Exosomal RBP4 (derived primarily from hepatocytes) promotes M1-like polarization of Kupffer cells via NOX2/ROS/NF-κB pathway activation, leading to TNFα overproduction. TNFα in turn activates JAK2/STAT3 in hepatocytes to increase RBP4 transcription, creating a positive feedback loop that promotes hepatic lipid accumulation and NAFLD progression. Intravenous RBP4 injection in high-fat diet mice recapitulates hepatic lipid accumulation and M1 Kupffer cell polarization. Exosome isolation and characterization; in vitro co-culture of RBP4-treated Kupffer cells with hepatocytes; NOX2/NF-κB inhibition; Western blotting for JAK2/STAT3; intravenous RBP4 injection in HFD mice; lipogenesis gene expression analysis Free radical biology & medicine Medium 36572267
2024 RBP4 promotes denervation-induced skeletal muscle fat infiltration and atrophy through a STRA6/JAK2/STAT3-dependent pathway. Holo-RBP4 increases STRA6 expression (>3-fold), promotes JAK2/STAT3 phosphorylation, increases atrophy markers Atrogin-1 and MuRF1, and decreases myogenesis regulators MyoD and MyoG in C2C12 myotubes. RBP4 knockout mice are protected from denervation-induced muscle atrophy. Inhibition of STRA6/JAK2/STAT3 by siRNA or pharmacological inhibitors, or by the RBP4 antagonist A1120, reduces atrophy markers and protects against muscle atrophy in vivo. RBP4 knockout mice; intramuscular injection of apo- or holo-RBP4; siRNA targeting STRA6/JAK2/STAT3; pharmacological inhibitors; A1120 treatment; C2C12 myotube experiments; immunofluorescence; Western blotting Journal of cachexia, sarcopenia and muscle High 39031684
2023 Succinate triggers M2 polarization of macrophages via SUCNR1, and this polarization stimulates RBP4 secretion from macrophages. Secreted RBP4 then promotes endothelial tip cell formation and pathological angiogenesis via VEGFR2 signaling, linking macrophage metabolic state to vascular sprouting in ocular neovascularization. In vitro endothelial migration, invasion, and tubulation assays with macrophage-conditioned medium ± RBP4; SUCNR1 inhibition; choroidal neovascularization and oxygen-induced retinopathy mouse models; VEGFR2 pathway analysis Journal of neuroinflammation Medium 38129891
2018 RBP4 overexpression in canine hepatocytes is impaired by an amino acid deletion (K12del) near the RBP4 N-terminus that disrupts protein folding in vivo, reducing secretion from hepatocytes into serum. The maternal penetrance effect in congenital eye disease arises from impaired sequential retinol transfer across the placenta, dependent on RBP4 encoded by both maternal and fetal genomes. Genetic analysis of canine pedigree (homozygous K12del); in vivo hepatocyte secretion assay; serum RBP4 measurement; NMR/structural analysis of mutant protein folding (referenced in abstract) Cell reports Medium 29847795
2007 In zebrafish, rbp4 is expressed in the yolk syncytial layer (YSL) during early embryogenesis and is required for yolk extension and liver bud formation. Knockdown of Rbp4 in the YSL results in shortened yolk extension and formation of two liver buds, attributed to impaired liver progenitor cell migration. rbp4 expression in the YSL is negatively regulated by Nodal and Hedgehog signaling and positively by retinoic acid; rbp4 regulates extracellular matrix protein Fibronectin1 specifically in ventrolateral yolk. Morpholino-mediated knockdown of rbp4 in zebrafish YSL; in situ hybridization; pathway inhibition (Nodal, Hedgehog, retinoic acid); Fibronectin1 expression analysis BMC developmental biology Medium 17945029
2022 RBP4 promotes proliferation and migration of vascular smooth muscle cells (VSMCs) via the JAK2/STAT3 signaling pathway. RBP4 overexpression in VSMCs increases JAK2, STAT3, cyclinD1, and Bcl-2 levels and enhances VSMC proliferation and migration. Vitamin D supplementation reduces these RBP4-induced changes and inhibits abnormal VSMC proliferation. RBP4 overexpression plasmid transfection in VSMCs; vitamin D treatment; Western blotting for JAK2/STAT3/cyclinD1/Bcl-2; proliferation and migration assays; in vivo rat diabetic atherosclerosis model Oxidative medicine and cellular longevity Medium 35082965
2014 RBP4 enhances insulin-induced proliferation of vascular smooth muscle cells (RASMCs) and increases phosphorylation of ERK1/2 and JAK2. Blockade of ERK1/2 signaling with PD98059 inhibits RBP4-induced RASMC proliferation, whereas JAK2 inhibition with AG490 does not, identifying MAPK/ERK as the operative pathway for RBP4-induced VSMC proliferation in the context of hyperinsulinemia. RBP4 treatment of cultured rat aortic smooth muscle cells (RASMCs) ± insulin; ERK1/2 inhibitor (PD98059); JAK2 inhibitor (AG490); proliferation assay; Western blotting for p-ERK1/2 and p-JAK2 Endocrine Medium 24888764
2009 RBP4 is expressed in macrophages (but not undifferentiated monocytes) and expression increases during monocyte-to-macrophage differentiation. RBP4 expression in macrophages is strongly inhibited by TNF-α and LPS but not by IL-6, demonstrating that macrophages are novel sites of RBP4 expression regulated by inflammatory stimuli. Monocyte-to-macrophage differentiation assay; treatment with TNF-α, IL-6, LPS; qPCR for RBP4 expression Physiological research Low 19537932
2018 RBP4 overexpression in ovarian cancer cells promotes migration and proliferation, inducing MMP2 and MMP9 expression via the RhoA/Rock1 and ERK pathways. RBP4 knockdown reduces cancer cell migration, proliferation, and oncogenic factor expression. The pro-migratory effect depends on retinol/retinoic acid associated with RBP4. RBP4 overexpression and siRNA knockdown in ovarian cancer cells; Transwell migration assay; MMP2/MMP9 expression; RhoA/Rock1 inhibition; CyclinD1 Western blotting Journal of ovarian research Low 29642915

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance. Cell metabolism 237 24606904
2011 RBP4: a controversial adipokine. European journal of endocrinology 181 21835764
2007 Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects. Diabetologia 158 17294166
2008 RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome. Cell metabolism 155 18316031
2021 Biological Functions of RBP4 and Its Relevance for Human Diseases. Frontiers in physiology 152 33790810
2012 Liver retinol transporter and receptor for serum retinol-binding protein (RBP4). The Journal of biological chemistry 115 23105095
2013 Plasma retinol-binding protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses' health study. Circulation 106 23584360
2017 RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis. Stem cell reports 90 28689994
2007 Effects of genetic variation in the human retinol binding protein-4 gene (RBP4) on insulin resistance and fat depot-specific mRNA expression. Diabetes 81 17728376
2013 A1120, a nonretinoid RBP4 antagonist, inhibits formation of cytotoxic bisretinoids in the animal model of enhanced retinal lipofuscinogenesis. Investigative ophthalmology & visual science 78 23211825
2016 Hepatocytes Are the Principal Source of Circulating RBP4 in Mice. Diabetes 73 27797907
2011 Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. Diabetologia 71 21538175
2008 Effect of exercise training on A-FABP, lipocalin-2 and RBP4 levels in obese women. Clinical endocrinology 68 18710473
2008 Isoforms of retinol binding protein 4 (RBP4) are increased in chronic diseases of the kidney but not of the liver. Lipids in health and disease 65 18752671
2008 An RBP4 promoter polymorphism increases risk of type 2 diabetes. Diabetologia 64 18496666
2016 Antigen Presentation and T-Cell Activation Are Critical for RBP4-Induced Insulin Resistance. Diabetes 59 26936962
2015 Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease. Cell 58 25910211
2012 Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities. PloS one 56 23189188
2018 Adipokine RBP4 drives ovarian cancer cell migration. Journal of ovarian research 53 29642915
2014 The relationship of novel adipokines, RBP4 and omentin-1, with carotid atherosclerosis severity and vulnerability. Atherosclerosis 52 24956535
2020 RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 51 32167208
2006 Elevated serum RBP4 is associated with insulin resistance in women with polycystic ovary syndrome. Endocrine 50 17526940
2012 Coronary artery disease is associated with higher epicardial retinol-binding protein 4 (RBP4) and lower glucose transporter (GLUT) 4 levels in epicardial and subcutaneous adipose tissue. Clinical endocrinology 49 21645024
2009 Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma. Oncology reports 49 19288010
2009 Regulatory SNP in the RBP4 gene modified the expression in adipocytes and associated with BMI. Obesity (Silver Spring, Md.) 49 19851303
2016 Assessment of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Retinol-Binding Protein 4 (RBP4) in Type 2 Diabetic Patients with Nephropathy. Biomarker insights 48 26917947
2010 Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children. International journal of pediatric obesity : IJPO : an official journal of the International Association for the Study of Obesity 48 20950077
2022 Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells. Free radical biology & medicine 47 36572267
2018 Childhood retinol-binding protein 4 (RBP4) levels predicting the 10-year risk of insulin resistance and metabolic syndrome: the BCAMS study. Cardiovascular diabetology 47 29759068
2009 Macrophages are novel sites of expression and regulation of retinol binding protein-4 (RBP4). Physiological research 47 19537932
2018 Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein. Biochimica et biophysica acta. Molecular and cell biology of lipids 46 29414511
2009 The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis. BMC biology 46 19460132
2018 Liver-secreted RBP4 does not impair glucose homeostasis in mice. The Journal of biological chemistry 45 30126844
2015 RBP4 functions as a hepatokine in the regulation of glucose metabolism by the circadian clock in mice. Diabetologia 45 26564180
2014 Transthyretin Antisense Oligonucleotides Lower Circulating RBP4 Levels and Improve Insulin Sensitivity in Obese Mice. Diabetes 45 25524914
2015 Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M). European journal of human genetics : EJHG 38 26286643
2020 Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 37 32095874
2010 Association of retinol-binding protein-4 (RBP4) with lipid parameters in obese women. Obesity surgery 37 20544399
2012 Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: the significance of transthyretin. IUBMB life 34 23129325
2021 RBP4 Is Associated With Insulin Resistance in Hyperuricemia-Induced Rats and Patients With Hyperuricemia. Frontiers in endocrinology 30 34177800
2012 Are plasma levels of visfatin and retinol-binding protein 4 (RBP4) associated with body mass, metabolic and hormonal disturbances in women with polycystic ovary syndrome? European journal of obstetrics, gynecology, and reproductive biology 30 22397743
2016 Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background. Laboratory investigation; a journal of technical methods and pathology 29 26974396
2008 Effect of RBP4 gene variants on circulating RBP4 concentration and type 2 diabetes in a Chinese population. Diabetic medicine : a journal of the British Diabetic Association 29 18199128
2015 Association of RBP4 genetic variants with childhood obesity and cardiovascular risk factors. Pediatric diabetes 28 26611784
2012 Quantitative measurement of full-length and C-terminal proteolyzed RBP4 in serum of normal and insulin-resistant humans using a novel mass spectrometry immunoassay. Endocrinology 28 22253430
2011 High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 28 21324757
2009 Serum retinol-binding protein 4 (RBP4) and retinol in a cohort of borderline obese women with and without gestational diabetes. Clinical biochemistry 28 19857477
2008 Decreased hepatic RBP4 secretion is correlated with reduced hepatic glucose production but is not associated with insulin resistance in patients with liver cirrhosis. Clinical endocrinology 28 18466349
2007 Localized rbp4 expression in the yolk syncytial layer plays a role in yolk cell extension and early liver development. BMC developmental biology 28 17945029
2016 An investigation on the interaction modes of a single-strand DNA aptamer and RBP4 protein: a molecular dynamic simulations approach. Organic & biomolecular chemistry 27 27511589
2016 Retinol-binding protein 4 (RBP4) as the causative factor and marker of vascular injury related to insulin resistance. Postepy higieny i medycyny doswiadczalnej (Online) 27 28026829
2011 Human RBP4 adipose tissue expression is gender specific and influenced by leptin. Clinical endocrinology 27 21039728
2014 Association of urinary RBP4 with insulin resistance, inflammation, and microalbuminuria. European journal of endocrinology 26 24994759
2013 Long-term impact of vertical banded gastroplasty (VBG) on plasma concentration of leptin, soluble leptin receptor, ghrelin, omentin-1, obestatin, and retinol binding protein 4 (RBP4) in patients with severe obesity. Cytokine 25 24011638
2010 Associations of metabolic factors, especially serum retinol-binding protein 4 (RBP4), with blood pressure in Japanese--the Tanno and Sobetsu study. Endocrine journal 25 20798476
2018 Components of metabolic syndrome in relation to plasma levels of retinol binding protein 4 (RBP4) in a cohort of people aged 65 years and older. Journal of endocrinological investigation 24 29524177
2018 RBP4 regulates trophoblastic cell proliferation and invasion via the PI3K/AKT signaling pathway. Molecular medicine reports 24 30015949
2014 Proteomic Analysis of RBP4/Vitamin A in Children with Cleft Lip and/or Palate. Journal of dental research 24 24695672
2012 Serum FGF21 and RBP4 levels in patients with chronic hepatitis C. Scandinavian journal of gastroenterology 24 22670657
2021 LncRNA PTGS2 regulates islet β-cell function through the miR-146a-5p/RBP4 axis and its diagnostic value in type 2 diabetes mellitus. American journal of translational research 23 34786060
2017 Increased retinol-free RBP4 contributes to insulin resistance in gestational diabetes mellitus. Archives of gynecology and obstetrics 23 28528355
2022 Green Coffee Bean Extract Normalize Obesity-Induced Alterations of Metabolic Parameters in Rats by Upregulating Adiponectin and GLUT4 Levels and Reducing RBP-4 and HOMA-IR. Life (Basel, Switzerland) 22 35629362
2023 Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization. Journal of neuroinflammation 21 38129891
2017 Dietary weight loss-induced changes in RBP4, FFA, and ACE predict weight regain in people with overweight and obesity. Physiological reports 21 29122953
2009 Association of RBP4 gene variants and serum HDL cholesterol levels in the Newfoundland population. Obesity (Silver Spring, Md.) 21 19893506
2024 RBP4 promotes denervation-induced muscle atrophy through STRA6-dependent pathway. Journal of cachexia, sarcopenia and muscle 20 39031684
2020 The Role of Circulating RBP4 in the Type 2 Diabetes Patients with Kidney Diseases: A Systematic Review and Meta-Analysis. Disease markers 20 33082885
2020 Determination of FABP4, RBP4 and the MMP-9/NGAL complex in the serum of women with breast cancer. Oncology letters 20 33376518
2018 Elevated RBP4 plasma levels were associated with diabetic retinopathy in type 2 diabetes. Bioscience reports 20 30135138
2010 Non-additive effects of RBP4, ESR1 and IGF2 polymorphisms on litter size at different parities in a Chinese-European porcine line. Genetics, selection, evolution : GSE 20 20576168
2019 Relationships of SLC2A4, RBP4, PCK1, and PI3K Gene Polymorphisms with Gestational Diabetes Mellitus in a Chinese Population. BioMed research international 19 30805369
2023 Shift work is associated with an increased risk of type 2 diabetes and elevated RBP4 level: cross sectional analysis from the OHSPIW cohort study. BMC public health 18 37312059
2012 Valproic acid downregulates RBP4 and elicits hypervitaminosis A-teratogenesis--a kinetic analysis on retinol/retinoic acid homeostatic system. PloS one 18 23028466
2022 The Effects of RBP4 and Vitamin D on the Proliferation and Migration of Vascular Smooth Muscle Cells via the JAK2/STAT3 Signaling Pathway. Oxidative medicine and cellular longevity 17 35082965
2022 Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients. Nutrients 17 35631143
2020 Retinol and vitamin A metabolites accumulate through RBP4 and STRA6 changes in a psoriasis murine model. Nutrition & metabolism 17 31956331
2014 Increased RBP4 in a human model of activated anti-atherosclerotic and antiremodelling defences. European journal of clinical investigation 17 24739026
2014 Involvement of RBP4 in hyperinsulinism-induced vascular smooth muscle cell proliferation. Endocrine 17 24888764
2013 Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men. Obesity (Silver Spring, Md.) 17 23408763
2013 Interleukin-1β downregulates RBP4 secretion in human adipocytes. PloS one 17 23460908
2018 Serum RBP4 positively correlates with triglyceride level but not with BMI, fat mass and insulin resistance in healthy obese and non-obese individuals. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 16 29786448
2014 RBP4 gene variants are associated with insulin resistance in women with previous gestational diabetes. Disease markers 16 24665145
2014 A genetic polymorphism in RBP4 is associated with coronary artery disease. International journal of molecular sciences 16 25479076
2011 High plasma retinol binding protein 4 (RBP4) is associated with systemic inflammation independently of low RBP4 adipose expression and is normalized by transplantation in nonobese, nondiabetic patients with chronic kidney disease. Clinical endocrinology 16 21521262
2008 High circulating levels of RBP4 and mRNA levels of aP2, PGC-1alpha and UCP-2 predict improvement in insulin sensitivity following pioglitazone treatment of drug-naïve type 2 diabetic subjects. Journal of internal medicine 16 18324929
2021 Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin. Molecular biology reports 15 34041677
2014 First trimester placental retinol-binding protein 4 (RBP4) and pregnancy-associated placental protein A (PAPP-A) in the prediction of early-onset severe pre-eclampsia. Metabolism: clinical and experimental 15 25633269
2021 Systematic Quantification of Neurotrophic Adipokines RBP4, PEDF, and Clusterin in Human Cerebrospinal Fluid and Serum. The Journal of clinical endocrinology and metabolism 14 33484131
2021 A novel regulatory mechanism of geniposide for improving glucose homeostasis mediated by circulating RBP4. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 34856473
2020 Retinol-binding protein 4 (RBP4) and high sensitivity C-reactive protein (hs-CRP) levels in patients with diminished ovarian reserve (DOR): a cross-sectional study. Reproductive biology and endocrinology : RB&E 14 33198782
2018 Involvement of RBP4 in Diabetic Atherosclerosis and the Role of Vitamin D Intervention. Journal of diabetes research 14 30186876
2011 Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA). Clinica chimica acta; international journal of clinical chemistry 14 21406189
2019 Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses. Human genetics 13 31659433
2018 The preliminary association study of ADIPOQ, RBP4, and BCMO1 variants with polycystic ovary syndrome and with biochemical characteristics in a cohort of Polish women. Advances in medical sciences 13 29428584
2018 Maternal Inheritance of a Recessive RBP4 Defect in Canine Congenital Eye Disease. Cell reports 13 29847795
2017 Transgenic Mice Over-Expressing RBP4 Have RBP4-Dependent and Light-Independent Retinal Degeneration. Investigative ophthalmology & visual science 13 28813718
2024 Retinol-binding protein 4 (RBP4) circulating levels and gestational diabetes mellitus: a systematic review and meta-analysis. Frontiers in public health 12 38532976
2022 Effect of Upregulation of Transcription Factor TFDP1 Binding Promoter Activity Due to RBP4 g.36491960G>C Mutation on the Proliferation of Goat Granulosa Cells. Cells 12 35883591
2016 Association of RBP4 Genotype with Phenotypic Reproductive Traits of Sows. Genetics research international 12 26885398
2013 The effects of weight loss on FABP4 and RBP4 in obese women with metabolic syndrome. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 12 23979787

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