Review on NR1H4, with data on DNA/RNA, on the protein encoded and where the gene is implicated

Briz, O

Herraez, E

Marin, JJG

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

  
 
   
Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8) 571 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
INIST-CNRS 
 
OPEN ACCESS JOURNAL 
 
NR1H4 (nuclear receptor subfamily 1, group H, 
member 4) 
Oscar Briz, Elisa Herraez, Jose JG Marin 
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research 
Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain and National Institute of 
Health, Carlos III, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, 
Spain (OB, EH, JJGM), Department of Physiology and Pharmacology, University of Salamanca, 
Campus Miguel de Unamuno E.D. S-09, 37007 - Salamanca, Spain (JJGM) 
 
Published in Atlas Database: December 2013 
Online updated version : http://AtlasGeneticsOncology.org/Genes/NR1H4ID46032ch12q23.html 
DOI: 10.4267/2042/54011 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Abstract 
Review on NR1H4, with data on DNA/RNA, on the 
protein encoded and where the gene is implicated. 
Identity 
Other names: BAR, FXR, HRR-1, HRR1, RIP14 
HGNC (Hugo): NR1H4 
Location: 12q23.1 
DNA/RNA 
Description 
In humans, FXR is encoded by the NR1H4 gene, 
consisted of 11 exons and 10 introns. 
Transcription 
4 alternatively spliced transcript variants encoding 
different isoforms have been described for this 
gene. 
Variants 3 and 4 contain an alternate 5'-terminal 
exon resulting in isoforms FXRα2 longer than 
FXRα1, coding by variants 2 and 5, with a distinct 
N-terminus due to translation initiation from an 
alternate in-frame start codon in the exon 3.  
Use of an alternate in-frame donor splice site at 
exon 5 results in FXRα1(-) and FXRα2(-) variants 
that miss a 4 amino acid segment compared to 
FXRα1(+) and FXRα2(+) isoforms. 
Pseudogene 
A pseudogene of FXR has been located on 
chromosome 1 (1p13.1-1p13.3) (Pseudogene.org). 
 
A. NR1H4 gene structure. Schematic representation of the NR1H4 gene into 11 exons showing the alternative splicing and the 
start triplets that generate the 4 known isoforms. These have been classified according to the difference in the initial region of 
mRNA (α1 and α2) and the presence (+) or absence (-) of a 12-bp insert in the exon 5. 
NR1H4 (nuclear receptor subfamily 1, group H, member 4) Briz O, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8) 572 
 
B. NCBI reference sequences for FXR variants and isoforms. Variants 1 and 6, and variants 2 and 5 encode the same 
isoforms. 
 
Protein 
Note 
FXR is a ligand-activated transcription factor 
belonging to the nuclear receptor superfamily. 
Description 
FXR shares the typical structure of other nuclear 
receptors, including the N-terminal DNA binding 
domain (DBD) and the C-terminal ligand binding 
domain (LBD) (Modica et al., 2010).  
DBD contains two zinc fingers motifs involved in 
DNA binding and dimerization with RXRα.  
Hinge region connects the DBD with the LBD, and 
contains the insert of the amino acid sequence 
MYTG in the FXRα1/2(+) isoforms.  
Ligand-independent (AF-1) and -dependent (AF-2) 
transactivation domains involved in the interaction 
with co-repressors and co-activators are located in 
N- and C-termini, respectively. 
Expression 
FXR is expressed at high levels in the liver, small  
intestine, kidney and adrenal gland (Huber et al., 
2002). Lower FXR levels can be detected in other 
organs forming the gastrointestinal tract, pancreas, 
breast and endothelial cells.  
The liver predominantly expresses FXRα1(+/-), 
whereas FXRα2(+/-) are the most abundant 
isoforms in kidney and intestine. In all cases, the 
proportion of FXRα(1/2)(+) and FXRα(1/2)(-) 
isoforms is approximately 50% (Vaquero et al., 
2013b). 
Localisation 
When activated FXR translocates to the nucleus. 
Function 
Binding of bile acids, the natural ligands of FXR, to 
the receptor leads its translocation to the cell 
nucleus, formation of a heterodimer RXRα and 
binding to FXR response elements on DNA, which 
activates the transcription of its target genes. 
Among FXR target genes are those encoding most 
of the proteins involved in bile acid metabolism and 
transport (Modica et al., 2010). 
 
 
FXR isoforms. Schematic representation of FXR isoforms classified based on the presence of the exons 1 and 2 (FXRα1) or 3 
(FXRα2) in the initial region of the mRNA and the presence (+) or the absence (-) of the amino acid sequence MYTG in exon 5. 
AF1 and AF2: ligand-independent and -dependent transactivation domains, respectively; DBD: DNA binding domain; H: hinge 
region; LBD: ligand binding domain. 
NR1H4 (nuclear receptor subfamily 1, group H, member 4) Briz O, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8) 573 
 
Definition, nomenclature, and allelic frequency of clinically relevant NR1H4 genetic variants. MAF refers to the frequency 
at which the less common allele occurs in a given population according to the NCBI SNP database. Nucleotide positions refer to 
the ORF of the NM_005123 sequence. Amino acid positions refer to the NP_005114 (FXRα1(-)) or NP_001193921 (FXRα2(-)) 
proteins. AF-1, ligand-independent transactivation domain. 
 
Additional target genes have recently been 
described to be involved in FXR-mediated 
regulation of several body functions, such as 
prevention of hepatic and intestinal carcinogenesis, 
liver regeneration, intestinal barrier, attenuation of 
adverse effects of cholestasis, prevention of 
gallstone formation, and chemoprotection (Vaquero 
et al., 2013a). Some of the effects of FXR are 
mediated by the induction of the small heterodimer 
partner (SHP), a negative regulator encoded by the 
NR0B2 gene. This transcription factor interacts 
with other nuclear receptors blocking its activation. 
Glucocorticoids are able to directly activate FXR 
but they also antagonize the expression of FXR and 
its target genes (Rosales et al., 2013). 
Homology 
DBD domain is a highly conserved domain, 
whereas LBD domain is moderately conserved in 
sequence and highly conserved in structure between 
the various nuclear receptors (Modica et al., 2010). 
According to sequence homology NR1H4 has been 
included into the liver-X-receptor-like group of 
genes belonging to the thyroid hormone receptor-
like subfamily of nuclear receptors, together with 
NR1H2 (liver X receptor-β) and NR1H3 (liver X 
receptor-α). 
Mutations 
Note 
The presence of missense mutations in the NR1H4 
gene is unusual, suggesting an important role of this 
gene in the maintenance of organ function and 
cellular homeostasis. 
Somatic 
c.-1G>T is a common variation resulting in reduced 
translation efficiency (Marzolini et al., 2007) that 
might predispose to inflammatory bowel diseases 
(Attinkara et al., 2012) and intrahepatic cholestasis 
of pregnancy (Van Mil et al., 2007). c.-189-
1174G>A and c.-190+7064C>T are intronic SNP 
that have been associated with an altered glucose 
and lipid metabolism (Heni et al., 2013). c.1A>G 
and c.518T>C are two rare mutations in the coding 
sequence of FXR whose consequence is a reduction 
of the function of the protein. Both predispose to 
intrahepatic cholestasis of pregnancy (Van Mil et 
al., 2007).Implicated in 
Hepatocellular carcinoma and 
cholangiocarcinoma 
Note 
FXR is reduced in liver cancer suggesting that FXR 
is rather working as a tumour suppressor. Knockout 
mice for FXR spontaneously developed liver 
tumours after several months. A potential 
contribution of FXR in tumour suppression can be 
attributed to its anti-fibrogenic properties in liver. It 
has also been proposed a role of FXR in prevention 
of hepatocarcinogenesis by inhibiting the 
expression of gankyrin (PSMD10), which is 
activated in liver cancer and modifies the 
expression of tumour suppressor genes, including 
Rb, p53, C/EBPα, HNF4α, and p16. 
Colon cancer 
Note 
Emerging evidences support an important role for 
FXR in intestinal carcinogenesis. FXR mRNA 
expression is decreased in colonic polyps, and even 
more pronounced in colonic adenocarcinoma. Even 
before carcinomas have formed, FXR loss led to 
extensive mucosal infiltration of neutrophils and 
macrophages along with increased TNF-α mRNA 
expression and nuclear β-catenin accumulation. 
FXR deficiency led to increased susceptibility to 
tumour development by promoting WTN-β-catenin 
signalling through TNF-α released by infiltrated 
macrophages. In contrast to this indirect 
oncosupressive role of FXR, by maintaining 
intestinal epithelium integrity, FXR also carries out 
a direct oncosupressor activity. Thereby, several 
data suggest that FXR activation enhances 
apoptosis and inhibits cell proliferation by 
increasing the expression of proapoptotic genes 
NR1H4 (nuclear receptor subfamily 1, group H, member 4) Briz O, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8) 574 
including p21, BAK1, FADD, and repressing 
antiapoptotic genes, such as BCL-2. 
Chemoresistance 
Note 
Ligand-dependent and independent activation of 
FXR and/or its signalling pathway is involved in 
the chemoprotective response of liver cells.  
This is due in part to changes in the expression of 
several genes (ABCB4, TCEA2, CCL14, CCL15 
and KRT13) accounting for different MOC, mainly 
these involved in drug efflux (MOC-1b), DNA 
repair (MOC-4) and cell survival (MOC-5b). 
Moreover, this characteristic is shared by healthy 
and tumour cells, and hence may play an important 
role in enhancing the chemoprotection of healthy 
hepatocytes against genotoxic compounds and 
reducing the response of liver tumour cells to 
certain pharmacological treatments. 
Disease 
The development of chemoresistance depends on 
the expression of the genes involved in a variety of 
mechanisms of chemoresistance (MOC), which are 
present in both healthy tissues, where they are 
involved in the defence against the chemical stress 
caused by potentially toxic compounds, and in 
cancer cells, where they account for the poor 
response to antitumour drugs. 
Cholestasis 
Note 
FXR has a crucial role in maintaining bile acid 
homeostasis, especially during cholestasis. Upon 
activation by enhanced bile acid levels FXR 
mediates responses that partially protect the 
hepatocyte from the deleterious effect of 
accumulation of toxic bile acids.  
FXR inhibits bile acid synthesis in liver, through 
down-regulation of key enzymes in bile acid 
biosynthesis, such as CYP7A1 and CYP8B1. It also 
diminishes bile acid uptake by hepatocytes by 
repressing the expression of Na+-taurocholate 
cotransporting polypeptide or NTCP (gene symbol 
SLC10A1), and increases bile acid efflux by 
inducing the expression of ABC proteins at the 
canalicular membrane, such as including BSEP 
(ABCB11) and MDR3 (ABCB4) involved in bile 
acid-dependent phospholipid secretion. FXR up-
regulates the phase II enzymes uridine 5'-
diphosphate-glucuronosyltransferase 2B4 
(UGT2B4) and sulphotransferase 2A1 (SULT2A1), 
which glucuronidate or sulphate bile acids to render 
them more hydrophilic, less biologically active, and 
more easily to be eliminated from the body. In the 
intestine FXR-induced reduction of bile acid uptake 
by enterocytes due to transcriptional repression of 
ASBT (SLC10A2), which enhances bile acid faecal 
loss. Moreover, FXR increases the transcription of 
FGF19 in the ileum, triggering a signalling pathway 
that represses hepatic CYP7A1 expression, and 
hence down-regulation of bile acid synthesis. 
Disease 
Cholestasis, which is characterized by the 
accumulation of bile acids in liver and is associated 
with reduced detoxification capacity. 
Cirrhosis 
Note 
FXR is expressed in hepatic stellate cells, and its 
activation reduces the expression of extracellular 
matrix proteins by these cells, preventing liver 
fibrosis. 
Disease 
Cirrhosis is a result of advanced liver disease that is 
characterized by replacement of liver tissue by 
fibrosis and regenerative nodules, leading loss of 
liver function. 
Cholelithiasis 
Note 
FXR prevents gallstone formation by up-regulation 
of ABC proteins accounting for canalicular 
secretion of bile acids (BSEP) and phospholipids 
(MDR3), resulting in enhanced mixed micelle 
formation capability and, hence prevention of 
cholesterol crystallization in bile. 
Disease 
Cholelithiasis is a pathological situation 
characterized by presence in the gallbladder, of 
stones, a crystalline concretion formed by accretion 
of bile components. 
Hepatic regeneration 
Note 
FXR participates in bile acid-induced liver repair by 
promoting regeneration through regulation of the 
FoxM1b expression, a Forkhead Box transcription 
factor, which regulates cell cycle progression 
during liver regeneration. Moreover, FXR helps 
restoration of organ homeostasis. 
Disease 
Liver regeneration after loss of hepatic tissue is an 
adaptive response to repair injury consisting of 
induction of proliferative factors that activate the 
quiescent hepatocytes, followed by re-
establishment of normal liver size and renewed 
hepatocyte quiescence. 
Intestinal diseases 
Note 
FXR plays an important role in the protection 
against bacterial overgrowth and the maintenance 
of intestinal barrier function, and it has recently 
been involved in the pathogenesis of idiopathic 
inflammatory bowel disease. FXR activation in the 
intestinal tract decreases the production of 
proinflammatory cytokines such as IL1-β, IL-2, IL-
NR1H4 (nuclear receptor subfamily 1, group H, member 4) Briz O, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8) 575 
6, tumour necrosis factor-alpha (TNF-α) and 
interferon-gamma (IFN-γ), thus contributing to a 
reduction of inflammation and epithelial 
permeability. In addition, intestinal FXR activation 
induces the expression of genes with antibacterial 
properties involved in enteroprotection and 
prevention of bacterial translocation in the intestinal 
tract, including angiogenin, carbonic anhydrase 12 
or inducible nitric oxide synthase. 
Disease 
Intestinal bacterial proliferation and translocation, 
chronic diarrhoea and inflammatory bowel disease. 
Breakpoints 
Note 
NR1H4 gene is not involved in breakpoint regions. 
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This article should be referenced as such: 
Briz O, Herraez E, Marin JJG. NR1H4 (nuclear receptor 
subfamily 1, group H, member 4). Atlas Genet Cytogenet 
Oncol Haematol. 2014; 18(8):571-575. 


NR1H4 (nuclear receptor subfamily 1, group H, member 4)

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