Affinage

NR5A2

Nuclear receptor subfamily 5 group A member 2 · UniProt O00482

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR5A2 (LRH-1) is a monomeric orphan nuclear receptor that functions as a ligand-regulated transcription factor and pioneer factor, governing bile acid and cholesterol homeostasis, steroidogenesis, lipid metabolism, pluripotency, zygotic genome activation, and immune cell maturation. Its ligand-binding domain adopts a constitutively active conformation stabilized by an extended helix 2 and can bind signaling phosphatidylinositols such as PIP3, which allosterically modulate coregulator selectivity (PMID:12820970, PMID:26416531, PMID:26553876). Transcriptional output is fine-tuned by ERK-mediated phosphorylation of hinge-domain serines, SUMOylation at K289 that directs sequestration into PML nuclear bodies and recruitment of the corepressors PROX1 and N-CoR/GPS2, and SHP–SIRT1-dependent histone deacetylation at target promoters (PMID:16439367, PMID:15923626, PMID:25176150, PMID:20159957, PMID:20375098). NR5A2 acts as a pioneer factor during zygotic genome activation by using a conserved CTE loop in its DNA-binding domain to compete with nucleosomal minor-groove anchors, unwrapping entry–exit DNA to open chromatin at SINE B1/Alu elements and at lineage-specifying loci required for both ICM and trophectoderm gene programs (PMID:36423263, PMID:38409506, PMID:37935903, PMID:38243114).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2003 High

    How LRH-1 achieves constitutive transcriptional activity without a bound ligand was unknown; the crystal structure revealed an extended helix 2 that stabilizes an active LBD conformation with a large empty pocket, establishing the structural basis for ligand-independent activity.

    Evidence X-ray crystallography at 2.4 Å with site-directed mutagenesis of helix 2 arginine

    PMID:12820970

    Open questions at the time
    • Identity of endogenous regulatory ligands not established
    • No structure of full-length receptor
  2. 2004 Medium

    Which corepressors restrain LRH-1 activity was unclear; identification of Prox1 as an LRH-1 co-repressor and demonstration that LRH-1 directly binds the ABCG5/ABCG8 intergenic region established its role in cholesterol efflux gene regulation.

    Evidence Co-immunoprecipitation, reporter assays (Prox1); EMSA and promoter mutagenesis (ABCG5/G8)

    PMID:15121760 PMID:15143342

    Open questions at the time
    • Prox1–LRH-1 interaction mapped only by single-lab Co-IP and reporter
    • In vivo relevance of ABCG5/G8 regulation by LRH-1 not tested genetically
  3. 2005 High

    How post-translational modification controls LRH-1 subnuclear distribution was unknown; live-cell imaging showed SUMOylation dynamically sequesters LRH-1 into PML nuclear bodies, preventing chromatin access and target gene activation.

    Evidence FRET, FRAP, and fluorescence microscopy with SUMO-site mutants

    PMID:15923626

    Open questions at the time
    • Which SUMO E3 ligase targets LRH-1 in vivo not identified
    • Quantitative impact on target gene panels not assessed genome-wide
  4. 2006 High

    Whether mitogenic signaling modulates LRH-1 was untested; ERK1/2-dependent phosphorylation of hinge serines S238/S243 was shown to stimulate transactivation, linking growth factor pathways to LRH-1 output. Simultaneously, LRH-1 was found to drive intestinal glucocorticoid synthesis and to be required in extraembryonic tissues for primitive streak formation.

    Evidence In vitro kinase assay and phosphomimetic mutagenesis (ERK); haploinsufficient mice and steroidogenesis assays (intestinal GC); knockout with tetraploid aggregation rescue (gastrulation)

    PMID:16439367 PMID:16923850 PMID:17075876

    Open questions at the time
    • Upstream receptor-to-ERK pathway in physiological LRH-1 contexts not defined
    • Extraembryonic target genes mediating gastrulation rescue not identified
  5. 2010 High

    How SUMOylation mechanistically represses specific gene sets and whether LRH-1 has roles beyond metabolism were open questions; SUMOylation was shown to recruit LRH-1 and the N-CoR/GPS2 complex to acute-phase response promoters for transrepression, SHP–SIRT1 was found to deacetylate histones at bile acid synthesis genes, and LRH-1 was demonstrated to replace Oct4 in somatic cell reprogramming by activating Nanog.

    Evidence ChIP and Co-IP with SUMO-1 KO mice (transrepression); Co-IP and ChIP with dominant-negatives (SHP–SIRT1); retroviral reprogramming and genome-wide ChIP (iPSC)

    PMID:20096661 PMID:20159957 PMID:20375098

    Open questions at the time
    • Transrepression mechanism at APR genes not shown to be genome-wide
    • Whether LRH-1 directly opens chromatin during reprogramming not tested
  6. 2012 High

    How LRH-1 and HNF4α coordinately regulate Cyp7a1 was unclear; cooperative binding was shown to maintain basal expression and enable SHP-mediated FGF19 repression through histone mark remodeling.

    Evidence Hepatocyte-specific loss-of-function in mice with ChIP and histone mark analysis

    PMID:23038264

    Open questions at the time
    • Stoichiometric relationship and co-occupancy dynamics of LRH-1/HNF4α not resolved
  7. 2013 High

    Whether LRH-1 has tissue-maintenance roles beyond metabolism was uncertain; pancreatic Nr5a2 deletion caused acinar-to-ductal metaplasia and accelerated Kras-driven neoplasia, while neuron-specific deletion disrupted Kiss1-dependent reproductive axis control.

    Evidence Conditional pancreatic and kisspeptin-neuron knockout mice with disease and endocrine phenotyping

    PMID:23504956 PMID:23645620

    Open questions at the time
    • Direct versus indirect target genes in acinar maintenance not fully delineated
    • Whether Kiss1 regulation is the sole mechanism for reproductive phenotype not established
  8. 2014 High

    The in vivo consequences of LRH-1 SUMOylation and its broader cytoprotective functions were undefined; K289R knock-in mice showed reduced PROX1 interaction and enhanced reverse cholesterol transport (reducing atherosclerosis), LRH-1 was found to resolve ER stress via a Plk3→ATF2 pathway, and ovarian Nr5a2 loss impaired luteinization and progesterone synthesis.

    Evidence K289R knock-in mice with metabolic phenotyping; hepatic and Plk3 double-KO with rescue; granulosa-specific KO with steroidogenic analysis

    PMID:24552399 PMID:24737860 PMID:25176150

    Open questions at the time
    • Whether SUMO-PROX1 axis operates in tissues beyond liver not tested
    • Plk3–ATF2 pathway not confirmed outside hepatocytes
  9. 2015 High

    How phospholipid binding is transduced to coregulator selection and how LRH-1 participates in innate immunity were open; PIP3 was crystallized in the LBD pocket, an allosteric network linking the pocket to AF2 was mapped, and macrophage LRH-1 was shown to generate 15-HETE PPARγ ligands for alternative activation.

    Evidence X-ray crystallography and MD simulations (PIP3/allosteric); macrophage-specific KO with lipidomics and Candida infection model

    PMID:25873311 PMID:26416531 PMID:26553876

    Open questions at the time
    • Allosteric coregulator selectivity not validated by mutagenesis
    • In vivo PIP3 occupancy of LRH-1 not demonstrated
  10. 2017 High

    Downstream metabolic consequences of LRH-1 de-SUMOylation and its role in FasL-mediated immunity were unclear; K289R mice developed NAFLD through an LRH-1→OSBPL3→SREBP-1 lipogenic pathway, and LRH-1 was shown to directly activate the FASLG promoter controlling T cell cytotoxicity.

    Evidence K289R knock-in with siRNA rescue (NAFLD); FASLG promoter mutagenesis and pharmacological inhibition in hepatitis model

    PMID:28094767 PMID:28406481

    Open questions at the time
    • OSBPL3 regulation in human NAFLD not confirmed
    • FASLG regulation shown mainly in single lab
  11. 2018 High

    How NR5A2 loss triggers inflammation and what hepatic lipid species it controls were unresolved; ChIP-seq revealed NR5A2 undergoes a binding switch from differentiation to AP-1-dependent inflammatory genes (reversed by Jun deletion), and hepatic KO depleted arachidonoyl phospholipids via Elovl5/Fads2 repression.

    Evidence ChIP-seq with Jun conditional KO epistasis (pancreas); acute hepatic KO with lipidomics

    PMID:29438990 PMID:29443959 PMID:29515023

    Open questions at the time
    • Whether the NR5A2-to-AP-1 switch occurs in human pancreatic disease not established
    • Prostate steroidogenic role based on xenograft, not genetic model
  12. 2019 High

    Whether LRH-1 functions in adaptive immunity was unknown; T cell-specific deletion revealed LRH-1 is essential for T cell maturation, proliferation, and antiviral responses.

    Evidence T cell-specific conditional knockout mice with in vivo viral challenge

    PMID:31328159

    Open questions at the time
    • Direct transcriptional targets mediating T cell maturation not identified genome-wide
    • Mechanism of CD8+ T cell failure not molecularly defined
  13. 2021 High

    How NR5A2 sustains pluripotency at the chromatin level was incompletely understood; combined loss of Esrrb and Nr5a2 collapsed the pluripotency network by disrupting Oct4/Sox2/Nanog binding at co-occupied regulatory elements.

    Evidence Double-KO ESCs with ChIP-seq and transcriptomics

    PMID:34397088

    Open questions at the time
    • Whether Nr5a2 and Esrrb function redundantly or synergistically at individual loci not resolved
  14. 2022 High

    Whether a specific transcription factor drives zygotic genome activation was a central question in early development; Nr5a2 was identified as an essential pioneer factor for ZGA, binding SINE B1/Alu elements in cis-regulatory regions of ~72% of ZGA genes and opening chromatin on nucleosomal templates in vitro.

    Evidence De novo motif analysis, genetic loss-of-function, ATAC-seq, in vitro nucleosome binding, and chemical inhibition in mouse embryos

    PMID:36423263

    Open questions at the time
    • Whether NR5A2 is sufficient for ZGA or requires co-factors not determined
    • Human ZGA role not tested
  15. 2023 High

    Whether NR5A2 pioneer activity at ZGA is functionally linked to later lineage decisions was unknown; NR5A2 was shown to be dispensable for global 2-cell chromatin opening but essential for opening 8-cell-specific sites near pluripotency and trophectoderm genes, directly bridging ZGA to first lineage segregation.

    Evidence Nr5a2 knockout embryos with stage-resolved ChIP/CUT&TAG and ATAC-seq

    PMID:37935903

    Open questions at the time
    • Mechanism by which NR5A2 selects 8-cell-specific versus 2-cell sites not defined
  16. 2024 High

    The structural basis for NR5A2 pioneer factor activity and its role as a bipotency activator were unresolved; cryo-EM showed the CTE loop displaces a nucleosomal minor-groove anchor to unwrap DNA, and genetic studies confirmed NR5A2 activates both ICM and TE lineage genes at the 8-cell stage. A hepatic FXR-FGF4-FGFR4-LRH-1 signaling node was also defined as a first-line bile acid checkpoint.

    Evidence Cryo-EM with mutagenesis (pioneer mechanism); Tfap2c/Nr5a2 double-KO in embryos (bipotency); genetic mouse models with ChIP (FGF4-LRH-1 node)

    PMID:38243114 PMID:38409506 PMID:39393353

    Open questions at the time
    • Whether CTE-mediated unwrapping is sufficient for pioneer activity at all genomic loci not tested
    • Contribution of phospholipid ligands to pioneer function unknown
    • FXR-FGF4-LRH-1 axis not validated in human liver

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how NR5A2 selects different genomic targets across developmental stages, whether endogenous PIP3 occupancy regulates pioneer activity, and how the SUMOylation–corepressor switch is coordinated with pioneer factor function during lineage commitment.
  • No full-length NR5A2 structure available
  • In vivo phospholipid ligand identity and occupancy unresolved
  • Mechanism integrating post-translational modifications with pioneer activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4 GO:0008289 lipid binding 2
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-1430728 Metabolism 7 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3
Partners
ESRRBGPS2HNF4AJUNPROX1SHPSIRT1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Crystal structure of the LRH-1 ligand binding domain at 2.4 Å resolution reveals the receptor adopts an active conformation as a monomer with a large but empty hydrophobic pocket; constitutive activity is conferred by an extended helix 2 that provides an additional layer to the canonical LBD fold, and mutating the conserved arginine in helix 2 reduces LRH-1 activity and coregulator recruitment. X-ray crystallography and site-directed mutagenesis Molecular cell High 12820970
2015 Crystal structure of human LRH-1 ligand binding domain bound by PIP3 shows that the phospholipid hormone binds LRH-1 with high affinity, stabilizing the receptor LBD; the hydrophobic PIP3 tails are buried inside the ligand binding pocket while the negatively charged head group is presented on the receptor surface, establishing signaling phosphatidylinositols as regulatory ligands for LRH-1. X-ray crystallography and in vitro binding assay Journal of structural biology High 26416531
2024 Cryo-EM structure of human NR5A2 bound to a nucleosome shows that the conserved C-terminal extension (CTE) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome to release entry-exit site DNA; mutagenesis showed NR5A2 D159 of the CTE is dispensable for DNA binding but required for stable nucleosome association and persistent DNA unwrapping, defining a pioneer factor mechanism. Cryo-electron microscopy and mutational analysis Nature structural & molecular biology High 38409506
2005 SUMOylation of LRH-1 causes its exclusive localization to promyelocytic leukemia protein (PML) nuclear bodies in a dynamic process demonstrated by FRET and FRAP; desumoylation releases LRH-1 from PML bodies allowing access to actively transcribed target genes, showing that SUMO-dependent compartmentalization prevents LRH-1 from accessing chromatin. FRET, FRAP, and fluorescence microscopy with SUMO mutant analysis Molecular and cellular biology High 15923626
2006 Phosphorylation of LRH-1 hinge domain serine residues S238 and S243 by mitogenic signaling through ERK1/2 stimulates transactivation; alanine substitution at both sites decreases PMA-dependent LRH-1 transactivation, while aspartate substitutions (phosphomimetic) increase basal transactivation. In vitro kinase assay, site-directed mutagenesis, and transcriptional reporter assay The Journal of biological chemistry High 16439367
2014 SUMOylation of LRH-1 at K289 promotes interaction with the corepressor PROX1; mice carrying a SUMOylation-defective K289R mutation show decreased PROX1 interaction, increased reverse cholesterol transport gene expression, and develop less atherosclerosis on a high-cholesterol diet. Knock-in mouse model (K289R), co-immunoprecipitation, and metabolic phenotyping Cell metabolism High 25176150
2017 SUMOylation-defective LRH-1 K289R mutation induces OSBPL3 expression, which enhances SREBP-1 processing and promotes de novo lipogenesis; silencing hepatic Osbpl3 reverses the lipogenic phenotype of LRH-1 K289R mice, establishing a LRH-1 SUMOylation → OSBPL3 → SREBP-1 pathway in NAFLD. Knock-in mouse model, adenoviral gene expression, siRNA knockdown, and lipid analysis The Journal of clinical investigation High 28094767
2010 LRH-1 agonist-induced SUMOylation recruits LRH-1 to hepatic acute phase response (APR) promoters where it prevents clearance of the N-CoR corepressor complex upon cytokine stimulation; GPS2 functions as a transrepression mediator bridging SUMOylated LRH-1 to the N-CoR complex. ChIP, co-immunoprecipitation, SUMO-1 knockout mice, and promoter reporter assays Genes & development High 20159957
2010 The transcriptional corepressor SHP recruits SIRT1 histone deacetylase specifically to LRH-1 target gene promoters; SIRT1 deacetylates histones H3 and H4 at these promoters to repress LRH-1-dependent bile acid synthesis gene transcription (CYP7A1, SHP), in a manner dependent on SHP-SIRT1 interaction but not deacetylation of LRH-1 itself. Co-immunoprecipitation, ChIP, dominant-negative constructs, and reporter assays Nucleic acids research High 20375098
2012 HNF4α and LRH-1 cooperate in vivo to maintain basal Cyp7a1 expression and to enable SHP binding to the Cyp7a1 promoter, thereby facilitating FGF19-mediated repression of bile acid synthesis; HNF4α and LRH-1 promote active transcription histone marks on the Cyp7a1 promoter that are reversed by FGF19 in a SHP-dependent manner. Loss-of-function studies in mice, ChIP, and histone mark analysis The Journal of biological chemistry High 23038264
2014 LRH-1 initiates an ER stress resolution pathway independent of known UPR components by inducing expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2; Plk3-null mice cannot resolve ER stress, and restoring Plk3 in Lrh-1-null cells rescues ER stress resolution. Hepatic Lrh-1 knockout mice, Plk3 knockout mice, rescue experiments, and in vitro stress assays eLife High 24737860
2010 Nr5a2 (LRH-1) can replace Oct4 in reprogramming mouse somatic cells to iPSCs; it functions in part by activating Nanog expression and shares common genomic targets with Sox2 and Klf4 as revealed by genome-wide location analysis. Sumoylation mutants of Nr5a2 with enhanced transcriptional activity further increase reprogramming efficiency. Retroviral reprogramming, genome-wide ChIP analysis, and luciferase reporter assays Cell stem cell High 20096661
2022 Nr5a2 is an essential pioneer factor for zygotic genome activation (ZGA) in mouse two-cell embryos; it binds its motif within SINE B1/Alu retrotransposable elements in cis-regulatory regions of ZGA genes, promotes chromatin accessibility during ZGA, and binds nucleosomal DNA in vitro. Chemical inhibition indicates 72% of ZGA genes are regulated by Nr5a2. De novo motif search, knockout/knockdown, ATAC-seq, in vitro nucleosome binding, and chemical inhibition Science (New York, N.Y.) High 36423263
2023 NR5A2 bridges ZGA to the first lineage segregation in totipotent mouse embryos; it is not required for global chromatin opening at the 2-cell stage but is essential for opening 8-cell-specific binding sites near blastocyst/stem cell regulatory genes. NR5A2 directly regulates key pluripotency genes (Nanog, Pou5f1/Oct4) and trophectoderm genes (Tead4, Gata3) at the 8-cell stage. Nr5a2 knockout, genome-wide chromatin binding (ChIP/CUT&TAG), ATAC-seq, and transcriptome analysis Cell research High 37935903
2024 NR5A2 acts as a bipotency activator in totipotent embryos, binding and activating both early trophectoderm (TE) and inner cell mass (ICM) lineage genes at the 8-cell stage; Nr5a2 deficiency causes downregulation of both ICM genes (Nanog) and TE genes in 8-cell embryos. Tfap2c and Nr5a2 knockout, ChIP-seq in embryos, and transcriptome analysis Nature structural & molecular biology High 38243114
2004 The homeodomain protein Prox1 functions as a co-repressor for LRH-1/NR5A2, representing a conserved functional interaction analogous to the Drosophila FTZ/FTZ-F1 cofactor relationship; this interaction is proposed to regulate cholesterol homeostasis in the enterohepatic system. Co-immunoprecipitation, reporter assays, and functional characterization EMBO reports Medium 15143342
2004 LRH-1 binds a specific site at nucleotides 134-142 of the ABCG5/ABCG8 intergenic region, and this binding site is necessary for activity of both the ABCG5 and ABCG8 promoters; EMSA with HepG2 nuclear extracts confirmed LRH-1 binding, and overexpression increased promoter activity. EMSA, promoter mutagenesis, luciferase reporter assay Journal of lipid research Medium 15121760
2006 LRH-1 (NR5A2) promotes expression of steroidogenic enzymes and synthesis of corticosterone in murine intestinal epithelial cells; LRH-1 haplo-insufficiency strongly reduces intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress in vivo. LRH-1 haploinsufficient mice, in vitro steroidogenesis assays The Journal of experimental medicine High 16923850
2013 Nr5a2 maintains acinar cell differentiation and is required for re-establishing acinar fate during regeneration; Nr5a2 deletion in the pancreas leads to acinar-to-ductal metaplasia, loss of regenerative capacity, and dramatically accelerates oncogenic Kras-driven preneoplastic lesion development. Conditional pancreatic Nr5a2 knockout mice, caerulein pancreatitis, and Kras-driven cancer model Gut High 23645620
2018 NR5A2 links differentiation and inflammation in the pancreas by undergoing a transcriptional switch that relocates binding from differentiation-specific to inflammatory genes, promoting AP-1-dependent transcription; pancreatic deletion of Jun rescues the pre-inflammatory phenotype and NR5A2 binding to inflammatory gene promoters. Global transcriptomics, ChIP-seq, and Jun conditional knockout epistasis Nature High 29443959
2014 LRH-1 is required for luteinization in the female mouse ovary; Nr5a2 depletion from antral follicle granulosa cells permits formation of luteal-like structures but not functional corpora lutea, with reduced progesterone levels due in part to defects in cholesterol transport (down-regulation of Scarb1, Ldlr, and Star). Conditional granulosa-specific Nr5a2 knockout mice and steroidogenic pathway analysis Endocrinology High 24552399
2013 LRH-1 directly binds to the kisspeptin (Kiss1) promoter and stimulates Kiss1 transcription; deletion of LRH-1 from kisspeptin neurons decreases Kiss1 expression in the arcuate nucleus, reduces FSH levels, dysregulates follicle maturation, and prolongs the estrous cycle, while LRH-1 overexpression increases Kiss1 expression and FSH. Conditional neuron-specific knockout, overexpression, ChIP, and reporter assays Molecular endocrinology (Baltimore, Md.) High 23504956
2014 TNF suppresses intestinal glucocorticoid synthesis by activating c-Jun and NF-κB transcription factors, which both interact with NR5A2 and repress Cyp11a1 reporter activity; this repression is relieved by dominant-negative JNK1, IκB, or a JNK inhibitor. Reporter assay, co-immunoprecipitation, and mouse colitis model with pharmacological rescue Science signaling High 24570488
2015 LRH-1 mediates IL-13-induced macrophage polarization through generation of 15-HETE PPARγ ligands; LRH-1 loss-of-function in macrophages impairs generation of 15-HETE due to compromised regulation of CYP1A1 and CYP1B1, thereby blocking IL-13-induced alternative activation and increasing susceptibility to Candida albicans infection. LRH-1-deficient macrophage mice, lipid metabolite analysis, in vivo infection model Nature communications High 25873311
2015 X-ray crystallography and molecular modeling identify an allosteric network in LRH-1 that links phospholipid binding in the ligand binding pocket to an alternate activation function (AF) region encompassing the β-sheet-H6 region, which in turn communicates with the classical AF2 surface to dictate co-regulator selectivity. X-ray crystallography and molecular dynamics simulation The Journal of biological chemistry Medium 26553876
2016 NR5A2 controls neural stem cell fate decisions by synchronizing cell-cycle exit with neurogenesis induction and astrogliogenesis inhibition through direct regulatory effects on the Ink4/Arf locus, Prox1, Notch1, and JAK/STAT signaling pathways. Overexpression and loss-of-function in primary neural stem cells and mouse embryos Nature communications Medium 27447294
2006 NR5A2-null embryos display impaired primitive streak formation; aggregation experiments with wild-type tetraploid cells show that NR5A2 mutant epiblast cells can undergo normal gastrulation, demonstrating that NR5A2 is required specifically in extraembryonic tissues for proper primitive streak morphogenesis. Knockout mouse model and tetraploid aggregation rescue experiment Developmental dynamics High 17075876
2011 LRH-1 directly occupies aromatase promoter II (PII) in breast adipose stromal fibroblasts as shown by chromatin immunoprecipitation; shRNA knockdown of LRH-1 decreases both PII activity and total aromatase mRNA, demonstrating LRH-1 as a tissue-specific transcriptional driver of aromatase expression. Chromatin immunoprecipitation (ChIP) and shRNA knockdown Steroids Medium 21392518
2018 LRH-1 directly transactivates several key steroidogenic enzyme genes to promote de novo androgen biosynthesis in castration-resistant prostate cancer; pharmacological inhibition of LRH-1 attenuates LRH-1-mediated androgen elevation and reduces AR signaling in CRPC xenografts. Luciferase reporter assays, ChIP, xenograft models, and pharmacological inhibition Cancer research Medium 29438990
2021 Combined loss of Esrrb and Nr5a2 collapses the pluripotency network in mouse ESCs; the two orphan nuclear receptors occupy a large common set of regulatory elements and control the binding of Oct4, Sox2, and Nanog to DNA. Double knockout ESCs, ChIP-seq, and transcriptome analysis Development (Cambridge, England) High 34397088
2019 LRH-1 is expressed in T lymphocytes and is required for T cell maturation and function; T cell-specific deletion of LRH-1 causes loss of mature peripheral T cells, reduced CD4+ T cell proliferation, failure to mount immune responses, and CD8+ T cell failure to control viral infections. T cell-specific conditional knockout mice, in vitro and in vivo T cell functional assays Science advances High 31328159
2017 LRH-1/NR5A2 directly binds to binding sites in the FASLG promoter and drives FASLG promoter activity; mutations in LRH-1 binding sites reduce FASLG promoter activity, and pharmacological inhibition of LRH-1 decreases FasL expression and FasL-mediated T cell apoptosis and cytotoxicity. Luciferase reporter assay, promoter mutagenesis, pharmacological inhibition, and mouse hepatitis model Cell death & disease Medium 28406481
2022 LRH-1 regulates a PTGS2/COX2-PGE2-PTGER1 signaling axis in pancreatic islets; LRH-1 ablation in developing beta cells abolished BL001 agonist protection against apoptosis and blunted Ptgs2 induction, while PTGER1 antagonism negated LRH-1-mediated islet survival. Beta cell-specific conditional knockout, pharmacological agonist/antagonist, and islet survival assays iScience Medium 35602948
2018 LRH-1 is required for maintaining arachidonoyl (AA) phospholipid pools in the liver; hepatic LRH-1 knockout leads to large cytosolic lipid droplets, increased triglycerides, and reduced AA phospholipids due to repression of Elovl5 and Fads2 genes critical for AA biosynthesis. Acute hepatic knockout (AAV8-Cre), lipidomics, and genomic analysis JCI insight High 29515023
2024 Hepatic FXR-FGF4 paracrine signaling acts through an intracellular FGFR4-LRH-1 signaling node to downregulate Cyp7a1 and Cyp8b1; this liver-centric pathway serves as a first-line checkpoint for intrahepatic bile acid flux upstream of the peripheral FXR-FGF15/19 pathway. Genetic mouse models, pharmacological inhibition, and ChIP analysis Cell metabolism Medium 39393353

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell stem cell 380 20096661
2004 LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends in cell biology 348 15130581
1995 Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Developmental dynamics : an official publication of the American Association of Anatomists 305 8563022
1996 The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. Molecular and cellular biology 214 8668203
1999 The Drosophila beta FTZ-F1 orphan nuclear receptor provides competence for stage-specific responses to the steroid hormone ecdysone. Molecular cell 195 10078197
2010 GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response. Genes & development 155 20159957
2005 Zebrafish sex determination and differentiation: involvement of FTZ-F1 genes. Reproductive biology and endocrinology : RB&E 146 16281973
1993 Potential role for a FTZ-F1 steroid receptor superfamily member in the control of Drosophila metamorphosis. Proceedings of the National Academy of Sciences of the United States of America 145 8096644
2003 Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Molecular cell 139 12820970
2003 Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis. The Journal of biological chemistry 125 12837754
2013 Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 123 23645620
2022 Zygotic genome activation by the totipotency pioneer factor Nr5a2. Science (New York, N.Y.) 115 36423263
2000 nhr-25, the Caenorhabditis elegans ortholog of ftz-f1, is required for epidermal and somatic gonad development. Developmental biology 115 10772806
2012 Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo. The Journal of biological chemistry 113 23038264
2006 The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine. The Journal of experimental medicine 111 16923850
2018 Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 106 29443959
2016 Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression. Cell death & disease 94 27809310
1998 Cloning and characterization of a novel human hepatocyte transcription factor, hB1F, which binds and activates enhancer II of hepatitis B virus. The Journal of biological chemistry 92 9786908
2006 The competence factor beta Ftz-F1 potentiates ecdysone receptor activity via recruiting a p160/SRC coactivator. Molecular and cellular biology 89 17015464
1999 Medaka (Oryzias latipes) FTZ-F1 potentially regulates the transcription of P-450 aromatase in ovarian follicles: cDNA cloning and functional characterization. Molecular and cellular endocrinology 87 10375033
2013 Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRas(G12V)-driven pancreatic tumourigenesis. Gut 81 23598351
2013 Structure-based discovery of antagonists of nuclear receptor LRH-1. The Journal of biological chemistry 79 23667258
2004 The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter. Journal of lipid research 79 15121760
2004 The role of alpha1-fetoprotein transcription factor/LRH-1 in bile acid biosynthesis: a known nuclear receptor activator that can act as a suppressor of bile acid biosynthesis. The Journal of biological chemistry 76 14766742
2006 Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation. The Journal of biological chemistry 75 16439367
2005 SUMO-dependent compartmentalization in promyelocytic leukemia protein nuclear bodies prevents the access of LRH-1 to chromatin. Molecular and cellular biology 72 15923626
1997 Ftz-F1 is a cofactor in Ftz activation of the Drosophila engrailed gene. Development (Cambridge, England) 71 9043065
1996 Regulation of the EDG84A gene by FTZ-F1 during metamorphosis in Drosophila melanogaster. Molecular and cellular biology 70 8887679
2010 Emerging actions of the nuclear receptor LRH-1 in the gut. Biochimica et biophysica acta 66 21194563
2014 SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis by decreasing hepatic reverse cholesterol transport. Cell metabolism 65 25176150
2017 Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease. The Journal of clinical investigation 64 28094767
2015 Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Disease models & mechanisms 59 26398940
2014 Involvement of FTZ-F1 in the regulation of pupation in Leptinotarsa decemlineata (Say). Insect biochemistry and molecular biology 59 25446391
2014 Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution. eLife 57 24737860
2014 The orphan nuclear receptor Nr5a2 is essential for luteinization in the female mouse ovary. Endocrinology 55 24552399
2004 Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO reports 55 15143342
2015 Liver receptor homolog-1 (LRH-1): a potential therapeutic target for cancer. Cancer biology & therapy 54 25951367
2014 Molecular basis for the regulation of the nuclear receptor LRH-1. Current opinion in cell biology 54 25463843
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2013 Scavenger receptors mediate the role of SUMO and Ftz-f1 in Drosophila steroidogenesis. PLoS genetics 53 23637637
1993 FTZ-F1 beta, a novel member of the Drosophila nuclear receptor family. Mechanisms of development 53 8382937
1997 Molecular cloning of chicken FTZ-F1-related orphan receptors. Gene 52 9332374
2015 Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket. Journal of structural biology 50 26416531
2010 Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation. Nucleic acids research 49 20375098
2015 LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis. Nature communications 47 25873311
2023 NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos. Cell research 45 37935903
2018 LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity. JCI insight 44 29515023
2000 Developmental expression of a novel Ftz-F1 homologue, ff1b (NR5A4), in the zebrafish Danio rerio. Mechanisms of development 44 10704877
2024 Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress. Cell metabolism 43 39393353
2002 A functionally conserved member of the FTZ-F1 nuclear receptor family from Schistosoma mansoni. European journal of biochemistry 42 12423370
2008 Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1-reactive cytotoxic T cells. Blood 40 19074734
2018 Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis. Cancer research 39 29438990
2006 Nuclear receptor NR5A2 is required for proper primitive streak morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 39 17075876
2003 LRH-1/hB1F and HNF1 synergistically up-regulate hepatitis B virus gene transcription and DNA replication. Cell research 38 14728801
2014 LRH-1 governs vital transcriptional programs in endocrine-sensitive and -resistant breast cancer cells. Cancer research 37 24520076
2012 Genome-wide analysis of hepatic LRH-1 reveals a promoter binding preference and suggests a role in regulating genes of lipid metabolism in concert with FXR. BMC genomics 36 22296850
2024 Lineage regulators TFAP2C and NR5A2 function as bipotency activators in totipotent embryos. Nature structural & molecular biology 35 38243114
2014 Function of the nuclear receptor FTZ-F1 during the pupal stage in Drosophila melanogaster. Development, growth & differentiation 35 24611773
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2021 Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology. Biochimica et biophysica acta. Molecular basis of disease 34 33862147
2006 Transcriptional regulation of the rainbow trout CYP19a gene by FTZ-F1 homologue. The Journal of steroid biochemistry and molecular biology 34 16621513
2016 Nuclear receptor NR5A2 controls neural stem cell fate decisions during development. Nature communications 33 27447294
2017 Effect of NR5A2 inhibition on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers. Molecular carcinogenesis 32 27996162
2017 MicroRNA-374b reduces the proliferation and invasion of colon cancer cells by regulation of LRH-1/Wnt signaling. Gene 32 29128635
2016 Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. Developmental biology 32 27474396
2014 Tumor necrosis factor suppresses NR5A2 activity and intestinal glucocorticoid synthesis to sustain chronic colitis. Science signaling 32 24570488
2007 Impaired progesterone production in Nr5a2+/- mice leads to a reduction in female reproductive function. Biology of reproduction 32 17409375
2021 The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency. Development (Cambridge, England) 31 34397088
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2000 Zebrafish ftz-f1 gene has two promoters, is alternatively spliced, and is expressed in digestive organs. The Biochemical journal 30 10816440
2019 The Ovulatory Signal Precipitates LRH-1 Transcriptional Switching Mediated by Differential Chromatin Accessibility. Cell reports 29 31461657
2013 Nuclear receptor LRH-1 induces the reproductive neuropeptide kisspeptin in the hypothalamus. Molecular endocrinology (Baltimore, Md.) 29 23504956
2021 NF-κB Regulation of LRH-1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition-Associated Cholestasis. Hepatology (Baltimore, Md.) 28 34310734
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2020 Nuclear receptor Ftz-f1 promotes follicle maturation and ovulation partly via bHLH/PAS transcription factor Sim. eLife 26 32338596
2017 Juvenile hormone biosynthesis in adult Blattella germanica requires nuclear receptors Seven-up and FTZ-F1. Scientific reports 25 28074850
2011 Tissue-specific regulation of aromatase promoter II by the orphan nuclear receptor LRH-1 in breast adipose stromal fibroblasts. Steroids 25 21392518
1998 cDNA cloning of a new member of the FTZ-F1 subfamily from a rainbow trout. Biochimica et biophysica acta 25 9512659
2021 A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation. Scientific reports 24 33441767
2020 Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis. Cell death & disease 24 32111818
2020 GATA6 enhances the stemness of human colon cancer cells by creating a metabolic symbiosis through upregulating LRH-1 expression. Molecular oncology 23 32037723
2019 The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions. Science advances 23 31328159
2015 Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity. The Journal of biological chemistry 23 26553876
2018 Genome-Wide Screening and Functional Analysis Reveal That the Specific microRNA nlu-miR-173 Regulates Molting by Targeting Ftz-F1 in Nilaparvata lugens. Frontiers in physiology 22 30618850
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2024 Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition. Nature structural & molecular biology 20 38409506
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2020 Nuclear-mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog-1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer. IUBMB life 20 32931651
2019 Nr5a2 promotes tumor growth and metastasis of gastric cancer AGS cells by Wnt/beta-catenin signaling. OncoTargets and therapy 20 31114234
2017 Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions. Cell death & disease 20 28406481
2014 Cytoplasmic localization of Lrh-1 down-regulates ovarian follicular cyp19a1a expression in a teleost, the orange-spotted grouper Epinephelus coioides. Biology of reproduction 20 24943038
2013 NR5A2 regulates Lhb and Fshb transcription in gonadotrope-like cells in vitro, but is dispensable for gonadotropin synthesis and fertility in vivo. PloS one 20 23536856
2022 NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function. iScience 18 35602948
2020 Transcription factor FTZ-F1 regulates mosquito cuticular protein CPLCG5 conferring resistance to pyrethroids in Culex pipiens pallens. Parasites & vectors 18 33054862
2017 Ovary-specific depletion of the nuclear receptor Nr5a2 compromises expansion of the cumulus oophorus but not fertilization by intracytoplasmic sperm injection. Biology of reproduction 18 28520915
2016 The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival. Scientific reports 18 27586588
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1998 Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1. Molecular and cellular endocrinology 18 9722168
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