{"gene":"NR1H3","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Transient transfection/reporter assays, gel-shift/EMSA, heterodimer reconstitution","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of heterodimer, functional EMSA, reporter assays; foundational study replicated widely","pmids":["7744246"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Stable transfection of GR-RLD-1 chimeric construct with reporter gene; pharmacological inhibitors of PKA/PKC","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based reporter assay with pharmacological inhibitors in stably transfected cells; single lab, two orthogonal chemical perturbations","pmids":["9500983"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Reporter gene assays, RORα null (sg/sg) mouse analysis, LXRα/β double-knockout mouse analysis, promoter transfection","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic null mouse models combined with reporter assays, in vivo gene expression validation, multiple orthogonal methods","pmids":["18055760"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Transfection/reporter assay, EMSA, RT-PCR, western blot in JAR choriocarcinoma cells","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA demonstrates direct NR1H3/RXR binding to LXRE and reporter assays confirm functional activation; single lab, two orthogonal methods","pmids":["18276933"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Protein expression analysis, functional heterodimerization and transcriptional activation assays of wild-type vs. mutant NR1H3","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay of mutant vs. WT heterodimerization and transcriptional activity; single lab, mechanistic follow-up included","pmids":["27253448"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Transcriptomic screening, NR1H3 overexpression in HepaRG/iPSC cells, functional hepatocyte assays, NOD/SCID mouse transplantation model","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotypes and in vivo rescue; single lab, multiple functional readouts","pmids":["25073010"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP, luciferase reporter assay, chromatin immunoprecipitation, NR1H3 knockout mice with CLP model, RNA-seq","journal":"Bioengineering & translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, ChIP, and luciferase assays together with KO mouse model and RNA-seq; multiple orthogonal methods in single study","pmids":["37206244"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Immunofluorescence for subcellular localization; MTT assay, flow cytometry, RT-PCR, western blot in Ishikawa cells treated with TO901317","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence tied to functional cell-cycle outcome with multiple readouts; single lab","pmids":["30705597"],"is_preprint":false},{"year":2023,"finding":"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.","method":"NR1H3 knockout mice CLP model, NR1H3 agonist T0901317, western blot for AMPK/ACC, cardiac function measurements","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse epistasis combined with biochemical downstream readout (AMPK/ACC); single lab, two orthogonal approaches","pmids":["37085126"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Pharmacophore mapping, molecular docking and MD simulations (MM/GBSA), NR1H3 knockdown and overexpression, luciferase reporter assay, western blot, RNA-seq","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational binding + functional KD/OE with reporter and western blot validation; single lab, multiple orthogonal methods","pmids":["41241997"],"is_preprint":false},{"year":2011,"finding":"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.","method":"EMSA, luciferase reporter assay, B cell proliferation assay","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA identifies GATA-3 binding and luciferase confirms functional consequence; single lab, two orthogonal methods","pmids":["24886807"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Dual-luciferase reporter assay, EMSA/binding assay for FOXC1","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and luciferase assay demonstrating FOXC1 binding and functional promoter activity; single lab, two orthogonal methods","pmids":["36950018"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Single-cell transcriptomics, cross-species dataset integration (7 vertebrate species), functional analyses of NR1H3-dependent NF-κB suppression","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NR1H3-dependent suppression of NF-κB validated across species with scRNA-seq and functional assays; single study","pmids":["41957356"],"is_preprint":false}],"current_model":"NR1H3 (LXRα) is a nuclear receptor that heterodimerizes with RXR to bind LXREs and activate transcription of target genes involved in lipid/cholesterol homeostasis, immune regulation, and cell-cycle control; its activity is synergistically enhanced by PKA/PKC-dependent phosphorylation, mutually suppressed by RORα, and it directly represses NLRP3 inflammasome activity and the non-canonical NF-κB pathway, while specific promoter variants alter NR1H3 expression via differential binding of transcription factors GATA-3 and FOXC1."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1995,"claim":"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","pmids":["7744246"],"confidence":"High","gaps":["Endogenous physiological ligand not defined here","No structural basis for the LXRα-specific RXR activation"]},{"year":1998,"claim":"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","pmids":["9500983"],"confidence":"Medium","gaps":["Direct phosphorylation sites not mapped","Chimeric construct rather than full-length native receptor","Kinase-substrate relationship inferred pharmacologically"]},{"year":2007,"claim":"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","pmids":["18055760"],"confidence":"High","gaps":["Molecular mechanism of mutual suppression not resolved","Whether cross-repression occurs on shared elements unclear"]},{"year":2008,"claim":"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","pmids":["18276933"],"confidence":"Medium","gaps":["Physiological relevance in placenta not tested in vivo","Single cell-line context"]},{"year":2014,"claim":"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","pmids":["25073010"],"confidence":"Medium","gaps":["Direct NR1H3-HNF4α regulatory targets not delineated","Gain-of-function only"]},{"year":2016,"claim":"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","pmids":["27253448"],"confidence":"Medium","gaps":["Causal disease mechanism in CNS not established","Single lab functional characterization"]},{"year":2019,"claim":"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","pmids":["30705597"],"confidence":"Medium","gaps":["Whether cyclin repression is direct or indirect not resolved","Cytoplasmic localization not mechanistically explained"]},{"year":2023,"claim":"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","pmids":["37206244"],"confidence":"High","gaps":["Precise NLRP3 promoter/protein interaction mode not fully defined","Tissue specificity of repression unclear"]},{"year":2023,"claim":"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","pmids":["37085126"],"confidence":"Medium","gaps":["Direct link between NR1H3 transcription and AMPK activation not mechanistically defined","Single lab"]},{"year":2023,"claim":"Defined how a common promoter variant alters NR1H3 expression through differential FOXC1 binding.","evidence":"Dual-luciferase reporter and EMSA for FOXC1 at rs11039149","pmids":["36950018"],"confidence":"Medium","gaps":["In vivo expression consequence not measured","Disease association not functionally tested"]},{"year":2025,"claim":"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","pmids":["41957356"],"confidence":"Medium","gaps":["Direct NR1H3 targets in the NF-κB pathway not identified","Mechanism of repression not resolved"]},{"year":2025,"claim":"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","pmids":["41241997"],"confidence":"Medium","gaps":["Binding predicted computationally rather than co-crystallized","Physiological exposure relevance untested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NR1H3 on distinct target promoters","Cofactor/coregulator switching between programmes uncharacterized","Endogenous ligand-to-program coupling not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,4,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":["NR1H3/RXR heterodimer"],"partners":["RXR","RORA","HNF4A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13133","full_name":"Oxysterols receptor LXR-alpha","aliases":["Liver X receptor alpha","Nuclear receptor subfamily 1 group H member 3"],"length_aa":447,"mass_kda":50.4,"function":"Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity (PubMed:19481530, PubMed:25661920, PubMed:37478846). Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES (PubMed:37478846). LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides (By similarity). Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (PubMed:19481530). Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Induces LPCAT3-dependent phospholipid remodeling in endoplasmic reticulum (ER) membranes of hepatocytes, driving SREBF1 processing and lipogenesis (By similarity). Via LPCAT3, triggers the incorporation of arachidonate into phosphatidylcholines of ER membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. Via LPCAT3 also counteracts lipid-induced ER stress response and inflammation, likely by modulating SRC kinase membrane compartmentalization and limiting the synthesis of lipid inflammatory mediators (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13133/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR1H3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR1H3","total_profiled":1310},"omim":[{"mim_id":"618556","title":"ENERGY HOMEOSTASIS-ASSOCIATED PROTEIN; ENHO","url":"https://www.omim.org/entry/618556"},{"mim_id":"617870","title":"CENTROSOMAL PROTEIN 350; CEP350","url":"https://www.omim.org/entry/617870"},{"mim_id":"613574","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 39B; TTC39B","url":"https://www.omim.org/entry/613574"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"611546","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 6; ELOVL6","url":"https://www.omim.org/entry/611546"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":84.3}],"url":"https://www.proteinatlas.org/search/NR1H3"},"hgnc":{"alias_symbol":["LXR-a","RLD-1","LXRa"],"prev_symbol":[]},"alphafold":{"accession":"Q13133","domains":[{"cath_id":"3.30.50.10","chopping":"93-182","consensus_level":"medium","plddt":93.4059,"start":93,"end":182},{"cath_id":"1.10.565.10","chopping":"207-442","consensus_level":"high","plddt":94.576,"start":207,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13133","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13133-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13133-F1-predicted_aligned_error_v6.png","plddt_mean":80.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR1H3","jax_strain_url":"https://www.jax.org/strain/search?query=NR1H3"},"sequence":{"accession":"Q13133","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13133.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13133/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13133"}},"corpus_meta":[{"pmid":"7744246","id":"PMC_7744246","title":"LXR, a nuclear receptor that defines a distinct retinoid response pathway.","date":"1995","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7744246","citation_count":925,"is_preprint":false},{"pmid":"24794974","id":"PMC_24794974","title":"In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation.","date":"2014","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24794974","citation_count":152,"is_preprint":false},{"pmid":"18055760","id":"PMC_18055760","title":"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).","date":"2007","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18055760","citation_count":91,"is_preprint":false},{"pmid":"27253448","id":"PMC_27253448","title":"Nuclear Receptor NR1H3 in Familial Multiple Sclerosis.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/27253448","citation_count":73,"is_preprint":false},{"pmid":"18276933","id":"PMC_18276933","title":"Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18276933","citation_count":35,"is_preprint":false},{"pmid":"11480455","id":"PMC_11480455","title":"Genomic structure and mapping of human orphan receptor LXR alpha: upregulation of LXRa mRNA during monocyte to macrophage differentiation.","date":"2000","source":"Journal of atherosclerosis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/11480455","citation_count":32,"is_preprint":false},{"pmid":"35640818","id":"PMC_35640818","title":"Silibinin protects against sepsis and septic myocardial injury in an NR1H3-dependent pathway.","date":"2022","source":"Free radical biology & 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DNA-binding partner.\",\n      \"method\": \"Transient transfection/reporter assays, gel-shift/EMSA, heterodimer reconstitution\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of heterodimer, functional EMSA, reporter assays; foundational study replicated widely\",\n      \"pmids\": [\"7744246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection of GR-RLD-1 chimeric construct with reporter gene; pharmacological inhibitors of PKA/PKC\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based reporter assay with pharmacological inhibitors in stably transfected cells; single lab, two orthogonal chemical perturbations\",\n      \"pmids\": [\"9500983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Reporter gene assays, RORα null (sg/sg) mouse analysis, LXRα/β double-knockout mouse analysis, promoter transfection\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic null mouse models combined with reporter assays, in vivo gene expression validation, multiple orthogonal methods\",\n      \"pmids\": [\"18055760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Transfection/reporter assay, EMSA, RT-PCR, western blot in JAR choriocarcinoma cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA demonstrates direct NR1H3/RXR binding to LXRE and reporter assays confirm functional activation; single lab, two orthogonal methods\",\n      \"pmids\": [\"18276933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Protein expression analysis, functional heterodimerization and transcriptional activation assays of wild-type vs. mutant NR1H3\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay of mutant vs. WT heterodimerization and transcriptional activity; single lab, mechanistic follow-up included\",\n      \"pmids\": [\"27253448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptomic screening, NR1H3 overexpression in HepaRG/iPSC cells, functional hepatocyte assays, NOD/SCID mouse transplantation model\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotypes and in vivo rescue; single lab, multiple functional readouts\",\n      \"pmids\": [\"25073010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, luciferase reporter assay, chromatin immunoprecipitation, NR1H3 knockout mice with CLP model, RNA-seq\",\n      \"journal\": \"Bioengineering & translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, ChIP, and luciferase assays together with KO mouse model and RNA-seq; multiple orthogonal methods in single study\",\n      \"pmids\": [\"37206244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence for subcellular localization; MTT assay, flow cytometry, RT-PCR, western blot in Ishikawa cells treated with TO901317\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence tied to functional cell-cycle outcome with multiple readouts; single lab\",\n      \"pmids\": [\"30705597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"NR1H3 knockout mice CLP model, NR1H3 agonist T0901317, western blot for AMPK/ACC, cardiac function measurements\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse epistasis combined with biochemical downstream readout (AMPK/ACC); single lab, two orthogonal approaches\",\n      \"pmids\": [\"37085126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacophore mapping, molecular docking and MD simulations (MM/GBSA), NR1H3 knockdown and overexpression, luciferase reporter assay, western blot, RNA-seq\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational binding + functional KD/OE with reporter and western blot validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41241997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"EMSA, luciferase reporter assay, B cell proliferation assay\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA identifies GATA-3 binding and luciferase confirms functional consequence; single lab, two orthogonal methods\",\n      \"pmids\": [\"24886807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Dual-luciferase reporter assay, EMSA/binding assay for FOXC1\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and luciferase assay demonstrating FOXC1 binding and functional promoter activity; single lab, two orthogonal methods\",\n      \"pmids\": [\"36950018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell transcriptomics, cross-species dataset integration (7 vertebrate species), functional analyses of NR1H3-dependent NF-κB suppression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NR1H3-dependent suppression of NF-κB validated across species with scRNA-seq and functional assays; single study\",\n      \"pmids\": [\"41957356\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR1H3 (LXRα) is a nuclear receptor that heterodimerizes with RXR to bind LXREs and activate transcription of target genes involved in lipid/cholesterol homeostasis, immune regulation, and cell-cycle control; its activity is synergistically enhanced by PKA/PKC-dependent phosphorylation, mutually suppressed by RORα, and it directly represses NLRP3 inflammasome activity and the non-canonical NF-κB pathway, while specific promoter variants alter NR1H3 expression via differential binding of transcription factors GATA-3 and FOXC1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3]. 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 [#0], and its transactivation is synergistically amplified by PKA- and PKC-dependent phosphorylation signalling [#1]. NR1H3 directly activates promoters such as endoglin (ENG) in trophoblasts [#3] and, conversely, suppresses proliferative drivers, repressing cyclin D1 and cyclin E to inhibit endometrial carcinoma cell growth [#7]. 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 [#2]. NR1H3 also enforces an anti-inflammatory programme: it directly represses NLRP3 inflammasome activity in cardiomyocytes, limiting inflammation, oxidative stress, and apoptosis during sepsis [#6], acts through an NR1H3/AMPK axis to protect against septic myocardial injury [#8], and suppresses the non-canonical NF-κB pathway in macrophages across species [#12]. The R415Q variant that disrupts heterodimerization and transactivation links NR1H3 dysfunction to multiple sclerosis in affected families [#4]. Common promoter polymorphisms tune NR1H3 expression through differential binding of GATA-3 and FOXC1 [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Heterodimer reconstitution with EMSA and reporter assays\",\n      \"pmids\": [\"7744246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological ligand not defined here\", \"No structural basis for the LXRα-specific RXR activation\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that NR1H3 transcriptional activity is not autonomous but integrated with kinase signalling, as PKA/PKC activation synergistically enhances transactivation.\",\n      \"evidence\": \"GR-RLD-1 chimera reporter assays with pharmacological PKA/PKC inhibitors in stably transfected cells\",\n      \"pmids\": [\"9500983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation sites not mapped\", \"Chimeric construct rather than full-length native receptor\", \"Kinase-substrate relationship inferred pharmacologically\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined reciprocal cross-repression between NR1H3 and RORα, establishing a regulatory node balancing lipid/cholesterol gene networks in vivo.\",\n      \"evidence\": \"Reporter assays plus RORα-null and LXRα/β double-knockout mouse gene expression analysis\",\n      \"pmids\": [\"18055760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of mutual suppression not resolved\", \"Whether cross-repression occurs on shared elements unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a direct gene target by showing NR1H3/RXR binds the endoglin LXRE and activates its expression in trophoblasts.\",\n      \"evidence\": \"EMSA, reporter assay, RT-PCR and western blot in JAR cells with LXR agonist\",\n      \"pmids\": [\"18276933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance in placenta not tested in vivo\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a developmental/differentiation role, with NR1H3 driving hepatic maturation through an HNF4α reciprocal network and yielding functional hepatocyte-like cells.\",\n      \"evidence\": \"Overexpression in HepaRG/iPSC cells with functional hepatocyte assays and mouse transplantation rescue\",\n      \"pmids\": [\"25073010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR1H3-HNF4α regulatory targets not delineated\", \"Gain-of-function only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected NR1H3 dysfunction to human disease by demonstrating the R415Q variant disrupts heterodimerization and transactivation in multiple sclerosis families.\",\n      \"evidence\": \"Functional heterodimerization and transcriptional assays of WT vs. mutant NR1H3\",\n      \"pmids\": [\"27253448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal disease mechanism in CNS not established\", \"Single lab functional characterization\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked NR1H3 to cell-cycle control by showing agonist-activated receptor suppresses cyclin D1 and cyclin E to inhibit carcinoma proliferation.\",\n      \"evidence\": \"Immunofluorescence localization plus MTT, flow cytometry, RT-PCR and western blot in Ishikawa cells\",\n      \"pmids\": [\"30705597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cyclin repression is direct or indirect not resolved\", \"Cytoplasmic localization not mechanistically explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established NR1H3 as a direct anti-inflammatory repressor of the NLRP3 inflammasome, protective in cardiac sepsis.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase assays, NR1H3-knockout CLP mouse model and RNA-seq\",\n      \"pmids\": [\"37206244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise NLRP3 promoter/protein interaction mode not fully defined\", \"Tissue specificity of repression unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an NR1H3/AMPK signalling axis mediating protection against septic myocardial injury.\",\n      \"evidence\": \"NR1H3-knockout CLP mice, T0901317 agonist, AMPK/ACC western blots and cardiac function readouts\",\n      \"pmids\": [\"37085126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between NR1H3 transcription and AMPK activation not mechanistically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined how a common promoter variant alters NR1H3 expression through differential FOXC1 binding.\",\n      \"evidence\": \"Dual-luciferase reporter and EMSA for FOXC1 at rs11039149\",\n      \"pmids\": [\"36950018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo expression consequence not measured\", \"Disease association not functionally tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NR1H3's anti-inflammatory function to macrophage suppression of the non-canonical NF-κB pathway as an evolutionarily conserved programme.\",\n      \"evidence\": \"Cross-species single-cell transcriptomics and NR1H3-dependent functional analyses\",\n      \"pmids\": [\"41957356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR1H3 targets in the NF-κB pathway not identified\", \"Mechanism of repression not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed NR1H3 is a direct molecular target of an environmental toxicant, with bisphenol S binding reducing receptor levels and impairing Sertoli cell survival.\",\n      \"evidence\": \"Molecular docking/MD simulations plus NR1H3 knockdown/overexpression with luciferase and western blot in human Sertoli cells\",\n      \"pmids\": [\"41241997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding predicted computationally rather than co-crystallized\", \"Physiological exposure relevance untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NR1H3 on distinct target promoters\", \"Cofactor/coregulator switching between programmes uncharacterized\", \"Endogenous ligand-to-program coupling not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 4, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"NR1H3/RXR heterodimer\"],\n    \"partners\": [\"RXR\", \"RORA\", \"HNF4A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}