Affinage

NR1H3

Oxysterols receptor LXR-alpha · UniProt Q13133

Length
447 aa
Mass
50.4 kDa
Annotated
2026-06-10
33 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1H3 (LXRα) is a ligand-activated nuclear receptor that heterodimerizes with RXR to bind LXR response elements (LXREs) and drive transcription of target genes governing lipid homeostasis, immune regulation, and cell-cycle control (PMID:7744246, PMID:18276933). Within the heterodimer it renders RXR competent to respond to 9-cis retinoic acid as an active ligand-binding subunit rather than a silent DNA-binding partner (PMID:7744246), and its transactivation is synergistically amplified by PKA- and PKC-dependent phosphorylation signalling (PMID:9500983). NR1H3 directly activates promoters such as endoglin (ENG) in trophoblasts (PMID:18276933) and, conversely, suppresses proliferative drivers, repressing cyclin D1 and cyclin E to inhibit endometrial carcinoma cell growth (PMID:30705597). Its transcriptional output is mutually antagonized by RORα, which reciprocally inhibits LXRα activity, with loss of either receptor in mice derepressing the other's target genes and altering hepatic lipid handling (PMID:18055760). NR1H3 also enforces an anti-inflammatory programme: it directly represses NLRP3 inflammasome activity in cardiomyocytes, limiting inflammation, oxidative stress, and apoptosis during sepsis (PMID:37206244), acts through an NR1H3/AMPK axis to protect against septic myocardial injury (PMID:37085126), and suppresses the non-canonical NF-κB pathway in macrophages across species (PMID:41957356). The R415Q variant that disrupts heterodimerization and transactivation links NR1H3 dysfunction to multiple sclerosis in affected families (PMID:27253448). Common promoter polymorphisms tune NR1H3 expression through differential binding of GATA-3 and FOXC1 (PMID:24886807, PMID:36950018).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 High

    Established the fundamental mode of action by showing NR1H3 functions as an RXR heterodimer on a dedicated response element, and uniquely activates RXR as a true ligand-responsive subunit rather than a passive partner.

    Evidence Heterodimer reconstitution with EMSA and reporter assays

    PMID:7744246

    Open questions at the time
    • Endogenous physiological ligand not defined here
    • No structural basis for the LXRα-specific RXR activation
  2. 1998 Medium

    Showed that NR1H3 transcriptional activity is not autonomous but integrated with kinase signalling, as PKA/PKC activation synergistically enhances transactivation.

    Evidence GR-RLD-1 chimera reporter assays with pharmacological PKA/PKC inhibitors in stably transfected cells

    PMID:9500983

    Open questions at the time
    • Direct phosphorylation sites not mapped
    • Chimeric construct rather than full-length native receptor
    • Kinase-substrate relationship inferred pharmacologically
  3. 2007 High

    Defined reciprocal cross-repression between NR1H3 and RORα, establishing a regulatory node balancing lipid/cholesterol gene networks in vivo.

    Evidence Reporter assays plus RORα-null and LXRα/β double-knockout mouse gene expression analysis

    PMID:18055760

    Open questions at the time
    • Molecular mechanism of mutual suppression not resolved
    • Whether cross-repression occurs on shared elements unclear
  4. 2008 Medium

    Identified a direct gene target by showing NR1H3/RXR binds the endoglin LXRE and activates its expression in trophoblasts.

    Evidence EMSA, reporter assay, RT-PCR and western blot in JAR cells with LXR agonist

    PMID:18276933

    Open questions at the time
    • Physiological relevance in placenta not tested in vivo
    • Single cell-line context
  5. 2014 Medium

    Revealed a developmental/differentiation role, with NR1H3 driving hepatic maturation through an HNF4α reciprocal network and yielding functional hepatocyte-like cells.

    Evidence Overexpression in HepaRG/iPSC cells with functional hepatocyte assays and mouse transplantation rescue

    PMID:25073010

    Open questions at the time
    • Direct NR1H3-HNF4α regulatory targets not delineated
    • Gain-of-function only
  6. 2016 Medium

    Connected NR1H3 dysfunction to human disease by demonstrating the R415Q variant disrupts heterodimerization and transactivation in multiple sclerosis families.

    Evidence Functional heterodimerization and transcriptional assays of WT vs. mutant NR1H3

    PMID:27253448

    Open questions at the time
    • Causal disease mechanism in CNS not established
    • Single lab functional characterization
  7. 2019 Medium

    Linked NR1H3 to cell-cycle control by showing agonist-activated receptor suppresses cyclin D1 and cyclin E to inhibit carcinoma proliferation.

    Evidence Immunofluorescence localization plus MTT, flow cytometry, RT-PCR and western blot in Ishikawa cells

    PMID:30705597

    Open questions at the time
    • Whether cyclin repression is direct or indirect not resolved
    • Cytoplasmic localization not mechanistically explained
  8. 2023 High

    Established NR1H3 as a direct anti-inflammatory repressor of the NLRP3 inflammasome, protective in cardiac sepsis.

    Evidence Co-IP, ChIP, luciferase assays, NR1H3-knockout CLP mouse model and RNA-seq

    PMID:37206244

    Open questions at the time
    • Precise NLRP3 promoter/protein interaction mode not fully defined
    • Tissue specificity of repression unclear
  9. 2023 Medium

    Identified an NR1H3/AMPK signalling axis mediating protection against septic myocardial injury.

    Evidence NR1H3-knockout CLP mice, T0901317 agonist, AMPK/ACC western blots and cardiac function readouts

    PMID:37085126

    Open questions at the time
    • Direct link between NR1H3 transcription and AMPK activation not mechanistically defined
    • Single lab
  10. 2023 Medium

    Defined how a common promoter variant alters NR1H3 expression through differential FOXC1 binding.

    Evidence Dual-luciferase reporter and EMSA for FOXC1 at rs11039149

    PMID:36950018

    Open questions at the time
    • In vivo expression consequence not measured
    • Disease association not functionally tested
  11. 2025 Medium

    Extended NR1H3's anti-inflammatory function to macrophage suppression of the non-canonical NF-κB pathway as an evolutionarily conserved programme.

    Evidence Cross-species single-cell transcriptomics and NR1H3-dependent functional analyses

    PMID:41957356

    Open questions at the time
    • Direct NR1H3 targets in the NF-κB pathway not identified
    • Mechanism of repression not resolved
  12. 2025 Medium

    Showed NR1H3 is a direct molecular target of an environmental toxicant, with bisphenol S binding reducing receptor levels and impairing Sertoli cell survival.

    Evidence Molecular docking/MD simulations plus NR1H3 knockdown/overexpression with luciferase and western blot in human Sertoli cells

    PMID:41241997

    Open questions at the time
    • Binding predicted computationally rather than co-crystallized
    • Physiological exposure relevance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NR1H3 transcriptional output is mechanistically partitioned between its lipid-homeostatic, anti-inflammatory, and cell-cycle programmes — and the structural/cofactor basis for context-specific target selection — remains unresolved.
  • No structural model of NR1H3 on distinct target promoters
  • Cofactor/coregulator switching between programmes uncharacterized
  • Endogenous ligand-to-program coupling not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1430728 Metabolism 1
Partners
HNF4ARORARXR
Complex memberships
NR1H3/RXR heterodimer

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 LXRα (NR1H3) forms a heterodimer with endogenous RXR that binds a distinct response element (LXRE) and mediates 9-cis retinoic acid (9cRA)-driven transcriptional activation; unlike RXR/RAR heterodimers, the LXRα/RXR complex renders RXR competent to respond to retinoids as an active ligand-binding subunit rather than a silent DNA-binding partner. Transient transfection/reporter assays, gel-shift/EMSA, heterodimer reconstitution Genes & development High 7744246
1998 Ligand-activated RLD-1 (NR1H3) transactivation is synergistically enhanced by agents that trigger PKA and PKC signalling pathways (PGE2, TPA, 8-bromo-cAMP, forskolin), and this enhancement is blocked by protein kinase inhibitors H-89 and bisindolylmaleimide, indicating that NR1H3 transcriptional activity is modulated by phosphorylation-dependent signal transduction. Stable transfection of GR-RLD-1 chimeric construct with reporter gene; pharmacological inhibitors of PKA/PKC Biochemical and biophysical research communications Medium 9500983
2007 NR1H3 (LXRα) and RORα mutually suppress each other's transcriptional activity: LXRα suppresses RORα-mediated Cyp7b1 promoter activation, and RORα inhibits both constitutive and ligand-dependent LXRα activity; loss of RORα in vivo increases expression of LXRα target genes leading to hepatic triglyceride accumulation, and LXRα/β-deficient mice show activation of RORα target genes. Reporter gene assays, RORα null (sg/sg) mouse analysis, LXRα/β double-knockout mouse analysis, promoter transfection Molecular pharmacology High 18055760
2008 NR1H3 (LXRα) directly activates the endoglin (ENG) gene promoter in human trophoblast cells by binding an LXRE as a heterodimer with RXR, increasing ENG mRNA and protein levels upon treatment with LXR agonist T0901317. Transfection/reporter assay, EMSA, RT-PCR, western blot in JAR choriocarcinoma cells Biology of reproduction Medium 18276933
2016 The NR1H3 p.Arg415Gln variant (found in MS families) disrupts NR1H3 heterodimerization and transcriptional activation of target genes, and mutant NR1H3 protein alters gene expression profiles consistent with disrupted transcriptional regulation. Protein expression analysis, functional heterodimerization and transcriptional activation assays of wild-type vs. mutant NR1H3 Neuron Medium 27253448
2014 Overexpression of NR1H3 in HepaRG cells promotes hepatic maturation (CYP enzyme activity, urea/albumin secretion, glycogen storage) through an HNF4α-dependent reciprocal regulatory network; NR1H3-derived hepatocyte-like cells rescued lethal fulminant hepatic failure in a mouse model. Transcriptomic screening, NR1H3 overexpression in HepaRG/iPSC cells, functional hepatocyte assays, NOD/SCID mouse transplantation model Journal of hepatology Medium 25073010
2023 NR1H3 directly represses NLRP3 inflammasome activity in cardiomyocytes; NR1H3 knockout worsens cardiac dysfunction and exacerbates NLRP3-mediated inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis in septic mice, whereas T0901317 agonist treatment reduces systemic infection and improves cardiac dysfunction. Co-IP, luciferase reporter assay, chromatin immunoprecipitation, NR1H3 knockout mice with CLP model, RNA-seq Bioengineering & translational medicine High 37206244
2019 NR1H3 is predominantly localized to the cytoplasm of Ishikawa endometrial carcinoma cells (by immunofluorescence); LXR agonist TO901317 activates NR1H3 and inhibits cell proliferation by suppressing cyclin D1 (CCND1) and cyclin E (CCNE) expression in a dose- and time-dependent manner. Immunofluorescence for subcellular localization; MTT assay, flow cytometry, RT-PCR, western blot in Ishikawa cells treated with TO901317 OncoTargets and therapy Medium 30705597
2023 NR1H3 activation by psoralidin protects against septic myocardial injury through an NR1H3/AMPK pathway; T0901317 activation of NR1H3 in HL-1 cardiomyocytes increases AMPK and ACC activity, and NR1H3 knockout abrogates psoralidin's protective effects in CLP mice. NR1H3 knockout mice CLP model, NR1H3 agonist T0901317, western blot for AMPK/ACC, cardiac function measurements Free radical biology & medicine Medium 37085126
2025 NR1H3 is a direct molecular target of bisphenol S (BPS) in human Sertoli cells; BPS binds NR1H3 (stable docking energy −20.64 kcal/mol confirmed by molecular dynamics), reduces NR1H3 protein levels and transcriptional activity, and NR1H3 knockdown impairs Sertoli cell survival while NR1H3 overexpression partially rescues BPS-induced cytotoxicity. Pharmacophore mapping, molecular docking and MD simulations (MM/GBSA), NR1H3 knockdown and overexpression, luciferase reporter assay, western blot, RNA-seq Ecotoxicology and environmental safety Medium 41241997
2011 GATA-3 transcription factor preferentially binds the −1830 T allele of the NR1H3 promoter (demonstrated by EMSA); the −1830 T>C polymorphism reduces NR1H3 promoter-driven luciferase activity under basal conditions and upon LXR agonist treatment, providing a mechanistic link between this variant and altered NR1H3 expression. EMSA, luciferase reporter assay, B cell proliferation assay Arthritis research & therapy Medium 24886807
2023 The rs11039149 A>G variant in the NR1H3 promoter disrupts binding of transcription factor FOXC1 (demonstrated by dual-luciferase and EMSA); the A allele allows FOXC1 binding and increases NR1H3 transcriptional activity, while the G variant abolishes FOXC1 binding and reduces transcriptional activity. Dual-luciferase reporter assay, EMSA/binding assay for FOXC1 Frontiers in pharmacology Medium 36950018
2025 NR1H3+ macrophages suppress the non-canonical NF-κB pathway in an NR1H3-dependent manner in both tree shrew and human macrophages; cross-species single-cell transcriptomic integration and functional analyses support an evolutionarily conserved anti-inflammatory programme mediated by NR1H3. Single-cell transcriptomics, cross-species dataset integration (7 vertebrate species), functional analyses of NR1H3-dependent NF-κB suppression Nature communications Medium 41957356

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes & development 925 7744246
2014 In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell metabolism 152 24794974
2007 Identification of oxysterol 7alpha-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor alpha (RORalpha) (NR1F1) target gene and a functional cross-talk between RORalpha and liver X receptor (NR1H3). Molecular pharmacology 91 18055760
2016 Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron 73 27253448
2008 Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR. Biology of reproduction 35 18276933
2000 Genomic structure and mapping of human orphan receptor LXR alpha: upregulation of LXRa mRNA during monocyte to macrophage differentiation. Journal of atherosclerosis and thrombosis 32 11480455
2022 Silibinin protects against sepsis and septic myocardial injury in an NR1H3-dependent pathway. Free radical biology & medicine 24 35640818
2020 Maternal fructose consumption down-regulates Lxra expression via miR-206-mediated regulation. The Journal of nutritional biochemistry 21 32388164
2013 Effects of NR1H3 genetic variation on the expression of liver X receptor α and the progression of Alzheimer's disease. PloS one 19 24278306
2014 Liver X receptors alpha gene (NR1H3) promoter polymorphisms are associated with systemic lupus erythematosus in Koreans. Arthritis research & therapy 17 24886807
2014 Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α. Journal of hepatology 17 25073010
2023 Activation of NR1H3 attenuates the severity of septic myocardial injury by inhibiting NLRP3 inflammasome. Bioengineering & translational medicine 16 37206244
2022 NR1H3 (LXRα) is associated with pro-inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b-cell lymphoma. Hematological oncology 16 35850118
2016 The association of NR1H3 gene with lipid deposition in the pig. Lipids in health and disease 16 27229308
2023 Activation of NR1H3 signaling pathways by psoralidin attenuates septic myocardial injury. Free radical biology & medicine 13 37085126
2018 Genetic variants regulate NR1H3 expression and contribute to multiple sclerosis risk. Journal of the neurological sciences 13 29801879
2021 The effect of N-Acetyl cysteine on the expression of Fxr (Nr1h4), LXRα (Nr1h3) and Sirt1 genes, oxidative stress, and apoptosis in the liver of rats exposed to different doses of cadmium. Molecular biology reports 12 33772418
2018 ENHO, RXRA, and LXRA polymorphisms and dyslipidaemia, related comorbidities and survival in haemodialysis patients. BMC medical genetics 12 30413149
1998 Synergistic activation of RLD-1 by agents triggering PKA and PKC dependent signalling. Biochemical and biophysical research communications 12 9500983
2023 Low expression of NR1H3 correlates with macrophage infiltration and indicates worse survival in breast cancer. Frontiers in genetics 11 36699456
2019 Expression of NR1H3 in endometrial carcinoma and its effect on the proliferation of Ishikawa cells in vitro. OncoTargets and therapy 5 30705597
2013 Nuclear receptor LXR: a new partner for sodium-dependent phosphate cotransporters. Contributions to nephrology 5 23652550
2024 An across breed, diet and tissue analysis reveals the transcription factor NR1H3 as a key mediator of residual feed intake in beef cattle. BMC genomics 4 38438858
2025 Uremic toxin receptor NR1H3 contributes to hyperlipidemia- and chronic kidney disease-accelerated vascular inflammation, which is partially suppressed by novel YBX2 anti-ROS pathway. Redox biology 3 40505347
2022 Expression of ABCA1 Transporter and LXRA/LXRB Receptors in Placenta of Women with Late Onset Preeclampsia. Journal of clinical medicine 3 36013052
2024 Decreased mRNA expression of NR1H3 and ABCA1 in pulmonary tuberculosis patients from population of Punjab, India. Molecular biology reports 1 38740636
2023 Pharmacogenetic association of the NR1H3 promoter variant with antihypertensive response among patients with hypertension: A longitudinal study. Frontiers in pharmacology 1 36950018
2022 New associations of serum β-carotene, lycopene, and zeaxanthin concentrations with NR1H3, APOB, RDH12, AND CYP genes. Food science & nutrition 1 35282004
2026 Tree shrew immune cell atlas identifies NR1H3⁺ tissue macrophages with conserved anti-inflammatory function. Nature communications 0 41957356
2026 A ceRNA axis of lncRNA MSTRG.14394.1/miR-144-3p/NR1H3 responds to diverse bacterial PAMPs in teleost fish. Fish & shellfish immunology 0 42103110
2025 Association between the rs2279238 and rs12221497 of the LXRA gene variants and diabetic retinopathy in the Slovenian cohort. Gene 0 40691909
2025 Bisphenol S disrupts human sertoli cell function through NR1H3 degradation: Mechanistic insights from integrated bulk and single-cell transcriptomics. Ecotoxicology and environmental safety 0 41241997
2023 Contributions of NR1H3 genetic polymorphisms to susceptibility and effects of narrowband UVB phototherapy to nonsegmental vitiligo. Scientific reports 0 36854764

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