NR1D1
a widely expressed member of the nuclear hormone receptor family of proteins. Transcriptional repressor which influence circadian rhythms, inflammatory responses and metabolic pathways in a heme-dependent manner. Lacks the activation function 2 domain required for ligand-dependent activation of transcription by other members of the nuclear receptor family; thus it behaves as a constitutive repressor protein, recruiting the nuclear receptor co-repressor N-CoR1/HDAC3 complex to target genes to repress transcription. Heme binding stimulates its interaction with the NCOR1/HDAC3 corepressor complex. Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Influences gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates malate dehydrogenase 1 (MDH1) and malic enzyme 1 (ME1), enzymes that link glycolysis and fatty acid synthesis. Its expression is increased in HER2-positive breast cancer cells, and may contribute to the abnormal cellular energy metabolism observed in HER2-positive breast cancers. Regulates inflammation by inhibiting the expression of Il17a and Il17f in TH17 cells, repressing the expression of inflammatory cytokines and chemokines in macrophages, and by targeting the NF-KB responsive genes IL-6 and COX-2. Elevated expression inhibits the progression of experimental autoimmune encephalomyelitis (EAE). Under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity. However, inflammation triggers its ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response. Its expression increases during differentiation in adipocytes and its ectopic expression in 3T3-L1 cells potentiates adipocyte differentiation. Its expression oscillates with circadian rhythm in liver cells, regulating the expression of BMAL1, ApoA1 and ApoC3, all key regulators of circadian rhythm. Represses the basal activity of the mouse Bmal1 gene promoter. Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system. Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Also expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and macrophages. Expressed at high levels in some squamous carcinoma cell lines. Belongs to the NR1 subfamily of nuclear receptors. Note: This description may include information from UniProtKB.
Protein type: Nuclear receptor; Transcription factor
Molecular Function: DNA-binding transcription factor activity, RNA polymerase II-specific; DNA-binding transcription repressor activity, RNA polymerase II-specific; E-box binding; heme binding; nuclear receptor activity; nuclear steroid receptor activity; protein binding; RNA polymerase II cis-regulatory region sequence-specific DNA binding; RNA polymerase II transcription regulatory region sequence-specific DNA binding; sequence-specific double-stranded DNA binding; transcription cis-regulatory region binding; transcription corepressor binding; zinc ion binding
Biological Process: cell differentiation; cellular response to interleukin-1; cellular response to lipopolysaccharide; cellular response to tumor necrosis factor; cholesterol homeostasis; circadian regulation of gene expression; circadian temperature homeostasis; glycogen biosynthetic process; hormone-mediated signaling pathway; intracellular glucose homeostasis; intracellular receptor signaling pathway; negative regulation of astrocyte activation; negative regulation of cold-induced thermogenesis; negative regulation of DNA-templated transcription; negative regulation of I-kappaB kinase/NF-kappaB signaling; negative regulation of inflammatory response; negative regulation of microglial cell activation; negative regulation of neuroinflammatory response; negative regulation of toll-like receptor 4 signaling pathway; negative regulation of transcription by RNA polymerase II; positive regulation of bile acid biosynthetic process; positive regulation of DNA-templated transcription; positive regulation of transcription by RNA polymerase II; proteasomal protein catabolic process; protein destabilization; regulation of circadian rhythm; regulation of circadian sleep/wake cycle; regulation of fat cell differentiation; regulation of insulin secretion involved in cellular response to glucose stimulus; regulation of lipid metabolic process; regulation of type B pancreatic cell proliferation; response to leptin; steroid hormone mediated signaling pathway
