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FLASH GENE
Symbol NR1H3 contributors: mct - updated : 23-08-2016
HGNC name nuclear receptor subfamily 1, group H, member 3
HGNC id 7966
Location 11p11.2      Physical location : 47.270.448 - 47.290.400
Synonym name liver X receptor, alpha/oxysterol receptor
Synonym symbol(s) LXRA, RLD1, RLD-1, LXR alpha, LXR
DNA
TYPE functioning gene
STRUCTURE 19.95 kb     9 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Binding site
text structure
  • functional LXR/RXR binding site upstream of the transcription initiation site
    • MAPPING cloned Y linked N status provisional
    Map pter - MDK - F2 - NR1H3 - MYBPC3 - cen
    Authors Unigene
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 - 1720 50 447 - 2005 16170053
  • also called LXRalpha1
  • might be the main isoform regulating adipocyte metabolism
  • could have a deleterious effect by increasing lipolysis, a process strongly associated to the development of insulin resistance and type 2 diabetes.
    • 9 splicing polyA site 1540 - 387 . expressed at lower levels compared with LXRalpha1 in most tissues . except dominant expression in testis 2005 16170053
  • lacking the first 45 amino acids of LXRalpha1
  • generated through the use of a novel promoter and first exon
  • heterodimerized with the retinoid X receptor
  • binding to LXR response elements
  • showing a reduced transcriptional activity relative to LXRalpha1, indicating that the N-terminal domain of LXRalpha is essential for its full transcriptional activity
  • also called LXRalpha2
    • 9 splicing 1558 - 402 . expressed at lower levels compared with LXRalpha1 in most tissues 2005 16170053
  • lacking 50 amino acids within the ligand binding domain
  • generated through alternative recognition of the 3'-splice site in exon 6
  • heterodimerized with the retinoid X receptor
  • binding to LXR response elements
  • being unable to bind ligand
  • being transcriptionally inactive
  • also called LXRalpha3
    		•
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveintestine   moderately
     liver   moderately
    Endocrineparathyroid   moderately
    Lymphoid/Immunespleen   moderately
    Nervousbrain   highly
    Reproductivefemale systemuteruscervix highly
     male systemprostate  highly
    Respiratorylung   moderately
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  predominantly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticplatelet Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an N terminal modulator domain
  • a central bipartite (class II C4) zinc finger DNA binding domain
  • a C terminal ligand binding domain of hormone receptor
    • conjugated PhosphoP
    mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to rattus Nr1h3 (91.7 pc)
    homolog to murine Nr1h3 (92.1 pc)
    Homologene
    FAMILY
  • nuclear hormone receptor family
  • NR1 subfamily
    • CATEGORY regulatory , DNA associated , receptor nuclear
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • acting as a tissue specific cofactor for RXRA, controlling lipid-inducible expression of APOE in macrophages and adipocytes
  • promoting cholesterol efflux into intestinal lumen via the ABCA1 transporter
  • coactivating CYP7A1
  • acting as a steroid and thyroid hormone receptor
  • acting as a transcription coactivator
  • nuclear oxysterol receptors with established roles in cholesterol, lipid, and carbohydrate metabolism
  • increases the transcription of genes involved in cholesterol efflux and disposal, such as ABCA1 (ATP-binding cassette transporter A1)
  • NR1H2, NR1H3 are negative regulators of cardiac growth and inflammation via suppressing NF-kappaB signalling in cardiomyocytes
  • induces the transcription of genes that protect cells from cholesterol overload
  • coactivator-binding surface of NR1H3, but not that of RXRA, is critically important for physical and functional interactions with NCOA1
  • new role for NR1H3 in phospholipid homeostasis (
  • NR1H2 and NR1H3 play a crucial role in control of insulin production and secretion in pancreatic beta-cells (
  • potentially NR1H2 as well as NR1H3 could play a crucial role in the regulation of energy homeostasis
  • NR1H2, NR1H3 play central roles in the transcriptional control of lipid metabolism
  • NR1H3 (liver X receptor) and PPARA are nuclear receptors that control the expression of genes involved in glucose and lipid homoeostasis
  • can act as an important inhibitor of TNFSF11-mediated osteoclast differentiation
  • is a ligand-activated transcription factor and plays an important role in regulation of lipid homoeostasis and inflammation
  • NR1H3, NR1H4 initiate formation of coated platelets
    • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    text
  • negative regulation of transcription
    • PATHWAY
    metabolism lipid/lipoprotein
    signaling
    a component
  • heterodimerizing with NR5A2 (LRH1) or NROB2 (SHP)
    • INTERACTION
    DNA binding
    RNA
    small molecule metal binding,
  • Zn2+
    • protein
  • NR0B1 is a corepressor of NR1H3, functioning as a negative regulator of lipogenic enzyme gene expression in liver
  • regulatory functions of AEBP1 on PPARG1 and NR1H3 transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation
  • binds to the proximal regions of the PLIN1 and LIPE promoters
  • interaction of NR1H3 with CORO2A requires SUMOylation (possible involvement of deSUMOylating enzymes in negatively regulating NR1H3 repression functions)
  • CIDEA binds to liver X receptors (NR1H2, NR1H3) and regulates their activity (could therefore be of importance for the regulation of metabolic processes in human adipose tissue)
  • MID1IP1 is a mediator for stimulation of lipogenesis by NR1H2, NR1H3 activation in the liver
  • suppressive action of PIAS1 on NR1H2, NR1H3-activated gene expression programs, particularly in lipogenesis
  • ASXL2 increased NR1H3 activity through direct interaction in the presence of the ligand, but ASXL1 suppressed ligand-induced NR1H3 transcriptional activity
  • inhibits IFNG -induced biological responses, and IFNG is a new molecular target of NR1H3
  • UFM1 could suppress foam cell formation via the NR1H3-dependent pathway
  • AJUBA binds to the hinge and the ligand binding domains of NR1H3 via its C-terminal tandem LIM motifs and enhances NR1H3 target gene expression in liver cells
  • OSBPL2 binds to liver X receptor (NR1H3) and is required for nuclear NR1H3 expression
  • CRTC1 directly interferes with the expression of genes regulated by lipogenic transcription factors, most prominently liver x receptor alpha (NR1H3)
  • EEPD1 is a novel NR1H2, NR1H3-regulated gene in macrophages and likely it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1
  • SLC2A5 is regulated by NR1H3
    • cell & other
  • binding to oxysterols and mediating feed-forward induction
    • REGULATION
    activated by oxysterols
    induced by 9 cis retinoic acids and others RA
    Other regulated by fatty acids
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility
    Variant & Polymorphism SNP , other
  • a single nucleotide polymorphism, rs2279238, and a common haplotype, CAAGCC, were associated with obesity phenotypes
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascular  
    for intervention in cardiovascular disease
    osteoarticularboneothers
    clinical use of an LXR agonist would not only affect reverse cholesterol transport and inflammatory pathways but could significantly and negatively affect bone remodeling
    ANIMAL & CELL MODELS
  • Lxra -/- mice failed to induce transcription of the gene encoding cholesterol 7-alpha-hydroxylase. this defect was associated with a rapid accumulation of large amounts of cholesterol in the liver and the regulation of several other crucial lipid metabolizing genes was also altered(Peet, 98)
  • mice lacking Nr1h2, Nr1h3 manifested a breakdown in self-tolerance and developed autoantibodies and autoimmune glomerulonephritis