NR1H3 (Liver X Receptor Alpha): A Master Regulator of Lipid Metabolism and Inflammation
Explore the NR1H3 gene, its protein product LXRα, associated diseases, tissue expression, mutations, and key pathways in lipid homeostasis and immune regulation.
Gene Information Card
| Symbol | NR1H3 |
|---|---|
| Full Name | Nuclear Receptor Subfamily 1 Group H Member 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 11q11.2 (GRCh38.p14) |
| NCBI Gene ID | 10062 ncbi.nlm.nih.gov/gene/10062 |
| Ensembl ID | ENSG00000025434 |
| UniProt ID | Q13133 |
| OMIM ID | 602423 |
| HGNC ID | 7966 |
| Aliases | LXR-a, LXRalpha, RLD-1, LXRA |
Description
The NR1H3 gene encodes the Liver X Receptor alpha (LXRα), a member of the nuclear receptor superfamily of ligand-activated transcription factors. LXRα functions as a cholesterol sensor, regulating the expression of genes involved in lipid metabolism, cholesterol efflux, fatty acid synthesis, and inflammation. It forms obligate heterodimers with retinoid X receptors (RXRs) and binds to LXR response elements (LXREs) in the promoter regions of target genes. Endogenous ligands include oxysterols such as 22(R)-hydroxycholesterol and 24(S)-hydroxycholesterol. LXRα plays a critical role in maintaining lipid homeostasis and modulating immune responses, making it a key therapeutic target for metabolic and inflammatory diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Atherosclerosis | LXRα activation promotes reverse cholesterol transport by upregulating ABCA1 and ABCG1, reducing foam cell formation and inflammation in macrophages. Loss of function or reduced expression can exacerbate atherosclerotic plaque development. | Evidence from mouse models (LXRα/β knockout) and human genetic association studies. (Source: NCBI Gene, OMIM) |
| Non-alcoholic Steatohepatitis (NASH) | LXRα regulates hepatic de novo lipogenesis via SREBP-1c. Hyperactivation can promote hepatic steatosis, while its role in inflammation and fibrosis is complex. Modulating LXRα activity is being explored as a therapeutic strategy. | Preclinical studies using LXR agonists and antagonists in mouse models of NASH. (Source: NCBI Gene, PubMed indexed literature) |
| Alzheimer's Disease | LXRα regulates the expression of ApoE and ABCA1, which are involved in cholesterol transport and amyloid-beta clearance in the brain. LXR agonists have been shown to reduce amyloid pathology in mouse models. | Studies in transgenic mouse models of Alzheimer's disease and human post-mortem brain tissue analysis. (Source: NCBI Gene, OMIM) |
| Inflammatory Bowel Disease (IBD) | LXRα exerts anti-inflammatory effects by inhibiting NF-κB signaling in macrophages and intestinal epithelial cells. Reduced LXRα activity may contribute to chronic intestinal inflammation. | Studies in mouse models of colitis and human IBD patient samples. (Source: PubMed indexed literature) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 35.6 | High |
| Adipose Tissue | 22.1 | Medium |
| Small Intestine | 18.4 | Medium |
| Macrophages (Spleen) | 15.2 | Medium |
| Kidney | 12.8 | Medium |
| Lung | 8.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (Liver) | 45.2 | High expression; used for studying lipid metabolism. |
| THP-1 (Monocyte/Macrophage) | 28.7 | High expression upon differentiation; key for cholesterol efflux studies. |
| Caco-2 (Colorectal) | 15.3 | Moderate expression; relevant for intestinal lipid absorption. |
| A549 (Lung) | 5.1 | Low expression. |
| MCF7 (Breast) | 3.8 | Low expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs7120118 | SNP (Intronic) | Minor allele frequency ~0.35 (C allele) | Associated with altered lipid profiles and increased risk of metabolic syndrome in some populations. |
| rs2279238 | SNP (Intronic) | Minor allele frequency ~0.20 (T allele) | Linked to variations in LXRα expression and response to lipid-lowering drugs. |
| p.Arg415Gln (rs61731969) | Missense Variant | Rare (MAF < 0.01) | Located in the ligand-binding domain; predicted to affect ligand binding affinity and transcriptional activity. |
Mutation functional classification
Loss of Function (LOF)
Complete loss-of-function mutations in NR1H3 are rare and often embryonic lethal in mice. In humans, partial loss-of-function variants that impair ligand binding or DNA binding can lead to dysregulated lipid metabolism, increased inflammation, and a higher risk of metabolic and cardiovascular diseases.
Gain of Function (GOF)
Gain-of-function mutations are uncommon. Constitutive activation of LXRα could lead to excessive lipogenesis in the liver, potentially contributing to hepatic steatosis. However, no clear gain-of-function mutations have been clinically characterized in humans.
Dominant Negative (DN)
Dominant-negative mutations have not been well-documented for NR1H3. However, a mutation that disrupts dimerization with RXR or coactivator recruitment could theoretically act in a dominant-negative manner, interfering with the function of the wild-type allele.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • Nuclear receptor activity | • Zinc ion binding |
| • Lipid binding | • Cholesterol binding |
| • Protein heterodimerization activity | • Sequence-specific DNA binding |
Pathways
• Cholesterol metabolism
• PPAR signaling pathway
• Fatty acid metabolism
• Regulation of lipid metabolism by LXR
• Inflammatory response pathway
• Reverse cholesterol transport
Protein Summary
The NR1H3 gene encodes Liver X Receptor alpha (LXRα), a 447-amino acid nuclear receptor. The protein consists of an N-terminal activation function-1 (AF-1) domain, a highly conserved DNA-binding domain (DBD) with two zinc finger motifs, a flexible hinge region, and a C-terminal ligand-binding domain (LBD) that also contains the activation function-2 (AF-2) domain. LXRα forms a permissive heterodimer with Retinoid X Receptor (RXR). Upon binding to oxysterol ligands, the receptor undergoes a conformational change, releasing corepressors and recruiting coactivators, leading to transcriptional activation of target genes. Key target genes include ABCA1, ABCG1, ApoE, SREBP-1c, and FASN. LXRα is a central regulator of cholesterol and fatty acid homeostasis and modulates inflammatory gene expression by tethering to and inhibiting transcription factors like NF-κB.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NR1H3 Knockout HEK293T Cell Line | EDJ-KQ109 | Human | 10062 | Details Get a Quote |
| NR1H3 Knockout HEK293 Cell Line | EDJ-KQ14490 | Human | 10062 | Details Get a Quote |
| NR1H3 Knockout A-549 Cell Line | EDJ-KQ44751 | Human | 10062 | Details Get a Quote |
| NR1H3 Knockout HCT 116 Cell Line | EDJ-KQ44752 | Human | 10062 | Details Get a Quote |
| NR1H3 Knockout HeLa Cell Line | EDJ-KQ44753 | Human | 10062 | Details Get a Quote |
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