NR1H4 (FXR) Gene: Nuclear Receptor Subfamily 1 Group H Member 4
A key regulator of bile acid, lipid, and glucose metabolism; implicated in cholestasis, metabolic disorders, and cancer.
Gene Information Card
| Symbol | NR1H4 |
|---|---|
| Full Name | nuclear receptor subfamily 1 group H member 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 12q23.1 |
| NCBI Gene ID | 9971 ncbi.nlm.nih.gov/gene/9971 |
| Ensembl ID | ENSG00000012504 |
| UniProt ID | Q96RI1 |
| OMIM ID | 603826 |
| HGNC ID | 7967 |
| Aliases | FXR, BAR, HRR1, MGC163396 |
Description
The NR1H4 gene encodes the farnesoid X receptor (FXR), a nuclear receptor that functions as a ligand-activated transcription factor. FXR is primarily activated by bile acids and regulates the expression of genes involved in bile acid synthesis, transport, and enterohepatic circulation. It also plays critical roles in lipid and glucose metabolism, inflammation, and liver regeneration. Mutations and dysregulation of NR1H4 are associated with cholestatic liver diseases, metabolic disorders, and certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Progressive familial intrahepatic cholestasis (PFIC) | Loss-of-function mutations in NR1H4 impair bile acid homeostasis, leading to cholestasis and liver damage. | ClinVar, OMIM |
| Intrahepatic cholestasis of pregnancy (ICP) | Variants in NR1H4 may contribute to altered bile acid metabolism, increasing susceptibility to ICP. | ClinVar, literature |
| Gallstone disease | FXR dysfunction affects bile acid composition and cholesterol solubility, promoting gallstone formation. | OMIM, literature |
| Metabolic syndrome | FXR regulates lipid and glucose metabolism; reduced FXR activity is linked to dyslipidemia, insulin resistance, and obesity. | Literature, NCBI |
| Hepatocellular carcinoma (HCC) | FXR expression is often downregulated in HCC; loss of FXR promotes inflammation and tumorigenesis. | COSMIC, literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High | Primary site of FXR expression |
| Intestine (small and large) | Moderate | Particularly in ileum and colon |
| Kidney | Low | Expression in renal tubules |
| Adrenal gland | Low | Detected in adrenal cortex |
| Pancreas | Low | Islet cells |
| Gallbladder | Moderate | Epithelial cells |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | High | Hepatocellular carcinoma cell line |
| Caco-2 (colon) | Moderate | Intestinal epithelial cells |
| Huh7 (liver) | High | Hepatocellular carcinoma cell line |
| A549 (lung) | Low | Lung carcinoma |
| MCF7 (breast) | Low | Breast adenocarcinoma |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1Val) | Missense | Rare | Loss of function; associated with PFIC |
| c.286C>T (p.Arg96Trp) | Missense | Rare | Loss of function; reduced transcriptional activity |
| c.1124G>A (p.Arg375His) | Missense | Rare | Loss of function; impaired ligand binding |
| c.1483C>T (p.Arg495Ter) | Nonsense | Rare | Loss of function; truncated protein |
| c.1700A>G (p.Tyr567Cys) | Missense | Rare | Loss of function; altered DNA binding |
Mutation functional classification
Loss of Function (LOF)
Most NR1H4 mutations are loss-of-function, leading to reduced FXR activity and impaired bile acid homeostasis, causing cholestasis and metabolic defects.
Gain of Function (GOF)
No well-characterized gain-of-function mutations have been reported for NR1H4.
Dominant Negative (DN)
Some missense mutations may exert dominant-negative effects by interfering with wild-type FXR function, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • zinc ion binding | • ligand-activated transcription factor activity |
| • steroid hormone receptor activity | • bile acid binding |
| • nuclear receptor activity | • transcription coregulator binding |
| • chromatin binding | • protein homodimerization activity |
Pathways
• Bile acid metabolism
• FXR and LXR regulation of lipid metabolism
• Nuclear receptor transcription pathway
• Metabolism of lipids and lipoproteins
• Cholesterol metabolism
• Insulin signaling
• Inflammatory response
Protein Summary
The FXR protein is a nuclear receptor of approximately 56 kDa, composed of an N-terminal DNA-binding domain, a hinge region, a ligand-binding domain, and a C-terminal activation domain. It forms homodimers and binds to FXR response elements (FXREs) in target gene promoters. Upon bile acid binding, FXR recruits coactivators and regulates transcription. FXR is essential for bile acid homeostasis, and its activity is modulated by post-translational modifications such as phosphorylation and acetylation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NR1H4 Knockout HEK293 Cell Line | EDJ-KQ13735 | Human | 9971 | Details Get a Quote |
| NR1H4 Knockout Hep 3B2.1-7 Cell Line | EDJ-KZ373 | Human | 9971 | Details Get a Quote |
| NR1H4 Knockout Huh-7 Cell Line | EDJ-KZ374 | Human | 9971 | Details Get a Quote |
| NR1H4 Knockout HeLa Cell Line | EDJ-KQ55290 | Human | 9971 | Details Get a Quote |
| NR1H4 Knockout A-549 Cell Line | EDJ-KQ63772 | Human | 9971 | Details Get a Quote |
| NR1H4 Knockout HCT 116 Cell Line | EDJ-KQ72231 | Human | 9971 | Details Get a Quote |
Displaying Records 1 To 6 Of 6 Records
