Oxysterols receptor LXR-alpha

Function

Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity. 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. 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. 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).

Classification

Family (Pfam)

PF00104 Hormone_recep, PF00105 zf-C4

InterPro

Liver_X_rcpt, NHR-like_dom_sf, Nucl_hrmn_rcpt_lig-bd, Nuclear_hormone_rcpt_NR1, Nuclear_hrmn_rcpt, Znf_hrmn_rcpt, Znf_NHR/GATA

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 7

• 1UHL X-ray 2.90A
• 3IPQ X-ray 2.00A
• 3IPS X-ray 2.26A
• 3IPU X-ray 2.40A
• 5AVI X-ray 2.70A
• 5AVL X-ray 2.80A
• 5HJS X-ray 1.72A

A predicted model is available from AlphaFold.

Gene Ontology · 51

• GO:0000785 chromatin
• GO:0005737 cytoplasm
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0043235 receptor complex
• GO:0090575 RNA polymerase II transcription regulator complex
• GO:0015485 cholesterol binding
• GO:0031490 chromatin DNA binding
• GO:0003677 DNA binding
• GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
• GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
• GO:0004879 nuclear receptor activity
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0032810 sterol response element binding
• GO:0000976 transcription cis-regulatory region binding
• GO:0008270 zinc ion binding
• GO:0043277 apoptotic cell clearance
• GO:0030154 cell differentiation
• GO:0071222 cellular response to lipopolysaccharide
• GO:0042632 cholesterol homeostasis
• GO:0009755 hormone-mediated signaling pathway
• GO:0030522 intracellular receptor signaling pathway
• GO:0055088 lipid homeostasis
• GO:0042789 mRNA transcription by RNA polymerase II
• GO:0010887 negative regulation of cholesterol storage
• GO:0120163 negative regulation of cold-induced thermogenesis
• GO:0050728 negative regulation of inflammatory response
• GO:0032369 negative regulation of lipid transport
• GO:0043031 negative regulation of macrophage activation
• GO:0010745 negative regulation of macrophage derived foam cell differentiation
• GO:0090188 negative regulation of pancreatic juice secretion
• GO:0048550 negative regulation of pinocytosis
• GO:0045861 negative regulation of proteolysis
• GO:1903573 negative regulation of response to endoplasmic reticulum stress
• GO:0090341 negative regulation of secretion of lysosomal enzymes
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0060336 negative regulation of type II interferon-mediated signaling pathway
• GO:0036151 phosphatidylcholine acyl-chain remodeling
• GO:0010875 positive regulation of cholesterol efflux
• GO:0032376 positive regulation of cholesterol transport
• GO:0045893 positive regulation of DNA-templated transcription
• GO:0045723 positive regulation of fatty acid biosynthetic process
• GO:0046889 positive regulation of lipid biosynthetic process
• GO:0034145 positive regulation of toll-like receptor 4 signaling pathway
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0010867 positive regulation of triglyceride biosynthetic process
• GO:0042752 regulation of circadian rhythm
• GO:0010883 regulation of lipid storage
• GO:0032570 response to progesterone
• GO:0055092 sterol homeostasis
• GO:0070328 triglyceride homeostasis

Drugs targeting this protein · 5

• HYODEOXYCHOLIC_ACID agonist
• BMS-852927 modulator
• ROVAZOLAC agonist
• LXR-623 agonist
• ABEQUOLIXRON agonist

Related proteins · sequence + function similarity

• Oxysterols receptor LXR-alpha 0.99
• Oxysterols receptor LXR-alpha 0.99
• Oxysterols receptor LXR-alpha 0.99
• Oxysterols receptor LXR-beta 0.91
• Oxysterols receptor LXR-beta 0.91
• Oxysterols receptor LXR-beta 0.89
• Nuclear receptor ROR-gamma 0.87
• Nuclear receptor ROR-gamma 0.86
• Oxysterols receptor LXR-beta 0.86
• Nuclear receptor ROR-gamma 0.86
• Gag polyprotein 0.85
• Nuclear receptor ROR-alpha B 0.84

Co-cited proteins · studied together in the literature

• Oxysterols receptor LXR-beta 1 shared papers
• G protein pathway suppressor 2 1 shared papers
• Nuclear receptor coactivator 2 1 shared papers
• Cell cycle and apoptosis regulator protein 2 1 shared papers
• Progesterone receptor 1 shared papers
• NAD-dependent protein deacetylase sirtuin-1 1 shared papers
• Vitamin D3 receptor 1 shared papers
• E3 ubiquitin-protein ligase UBR5 1 shared papers
• Retinoic acid receptor alpha 1 shared papers
• Glucocorticoid receptor 1 shared papers
• Retinoic acid receptor RXR-alpha 1 shared papers
• Estrogen receptor 1 shared papers

Literature · 7 cited papers

• UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability. Mol. Cell · 2023
• CCAR2 negatively regulates nuclear receptor LXRalpha by competing with SIRT1 deacetylase. J. Steroid Biochem. Mol. Biol. · 2015
• GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus. Mol. Cell · 2009
• Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature · 2006
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat. Genet. · 2004
• LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. · 1995