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FLASH GENE

Symbol

NR1H4

contributors: mct/npt/pgu - updated : 21-03-2018

HGNC name	nuclear receptor subfamily 1, group H, member 4
HGNC id	7967

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005123 11 - 2213 NP_005114 54.3 472 - 2017 28619996 NM_001206977 12 - 2492 NP_001193906 - 476 - 2017 28619996 NM_001206979 11 - 2325 NP_001193908 - 476 - 2017 28619996 NM_001206978 10 - 2172 NP_001193907 - 425 - 2017 28619996 NM_001206993 9 - 1907 NP_001193922 - 486 - 2017 28619996 NM_001206992 9 - 1895 NP_001193921 - 482 - 2017 28619996

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine       Homo sapiens   liver       highly Homo sapiens Endocrine adrenal gland         Homo sapiens Lymphoid/Immune lymph node         Homo sapiens Nervous brain         Homo sapiens Reproductive male system testis       Homo sapiens Urinary kidney tubule       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose       Homo sapiens Muscular smooth vessel     Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic platelet Homo sapiens Lymphoid/Immune   Homo sapiens Nervous oligodendrocyte Homo sapiens Fetal

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	receptor composed of a central bipartite (class II C4) zinc finger DNA binding domain
	a N terminal modulator domain
	a C terminal ligand binding domain of hormone receptor

mono polymer

heteromer , dimer

HOMOLOGY

Homologene

FAMILY	nuclear hormone receptor family
	NR1 subfamily

CATEGORY

regulatory , transcription factor , receptor nuclear

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome,euchromosome

basic FUNCTION	plays an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol
	role in the regulation of ALAS1 and, consequently, hepatic porphyrin and heme synthesis
	inhibiting CYP7A1 synthesis when bound to bile acids
	bile acid sensor regulating the expression of a number of genes the products of which control bile acid and cholesterol homeostasis
	regulated 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) expression in adrenocortical cells
	plays a central role in maintaining lipid and glucose homeostasis
	mediates important signaling functions of bile acids in diverse cell types including those residing in the vascular wall
	regulates expression of liver cystathionase (CSE), hydrogen sulfide production and hepatic microcirculation
	regulates adipocyte differentiation and function by regulating two counteracting pathways of adipocyte differentiation, the PPARG and WNT/CTNNB1 pathways
	role for NR1H4 in the modulation of osteoblast/adipocyte balance: its activation stimulates RUNX2-mediated osteoblastic differentiation of bone marrow stromal cells (BMSC), whereas its inhibition leads to an adipocyte-like phenotype
	contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters, and its activation also affects lipid and glucose metabolism, and can influence drug metabolism
	nuclear bile acid receptor controlling bile acid, lipid, and glucose homeostasis
	transrepresses the expression of genes involved in glycolysis in human hepatocytes
	positively regulates likely bone metabolism through both arms of the bone remodeling pathways, bone formation and resorption
	control steroid production, and also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors
	plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts
	regulates bile acid, lipid and glucose metabolism
	important role of NR1H4 in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses
	bile acids and NR1H4 play pivotal roles in sepsis via controlling the NLRP3 inflammasome
	is dispensable for oligodendroglial differentiation
	NR1H4 and GPBAR1 may play an important role in modulation of age-related kidney disease
	NR1H3, NR1H4 initiate formation of coated platelets
	NR1H4 and DDIT3 have critical functions in hepatic lipid metabolism
	bile acids have emerged as important for renal pathophysiology by activating NR1H4 and GPBAR1 and transcription factors relevant for lipid, cholesterol and carbohydrate metabolism, as well as genes involved in inflammation and renal fibrosis (

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

a component

heterodimerizing with RXRs(retinoic X receptors)

INTERACTION

DNA

RNA

small molecule

protein	interacting with DCN (activation in vascular smooth muscle cells)
	interacting with AGTR2 (upregulates AGTR2 expression at a transcriptional level and play a role in the NR1H4-mediated inhibition of ERK activation via upregulation of PTPN6)
	interacting with PTK2 (pivotal role for PTK2 in the process of NR1H4-induced and MMP9-dependent endothelial cell motility and vascular tube formation)
	co-localized with NR0B1 in the nucleus and acted as a negative regulator of NR1H4 through a physical interaction with NR1H4
	NR0B1 acts as a novel co-repressor of NR1H4 in the liver
	NR1H4-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases
	activation of NR1H4 induced hepatic CES1, and reduced the levels of hepatic and plasma triglyceride (TG) as well as plasma cholesterol in a CES1-dependent manner
	CDX2 transcription factor as a positive regulator of NR1H4 expression in the enterocytes
	NR1H4 controls the liver derived tumor suppressor HRG
	KDM1A is a novel histone-modifying enzyme in the orchestrated regulation mediated by NR1H4 and small heterodimer partner that reduces hepatic Bile acids (BAs) levels and protects the liver against BA toxicity
	NR1H4 controls DDIT3 expression in steatohepatitis
	NR1H4 plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis

cell & other

binding bile acids

REGULATION

activated by	retinoids,farnesol metabolites
	by bile acids such as chenodeoxycholic acid, or synthetic ligands such as GW4064

Other

phosphorylated by PRKCA (phosphorylation induced by PKCalpha directly modulates the ability of agonists to activate NR1H4)

ASSOCIATED DISORDERS

corresponding disease(s)

PFIC5

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   in the liver in PFIC1 with severe cholestasis constitutional     --low   GPBAR1 and NR1H4 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases constitutional     --over   of NR1H4, NR0B2, SLC10A1 and ABCB11 was significantly up-regulated in the non-alcoholic steatohepatitis (NASH) in comparison with simple steatosis (SS) patients

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	Src-mediated NR1H4 phosphorylation is a potential biomarker for Bile-acid-related enterohepatic diseases
Therapy target
	System Type Disorder Pubmed digestive     NR1H4 agonists may increase gallbladder fluid secretion through transcriptional activation of VIPR1, which may contribute to the regulation of bile secretion by bile salts and to a protective effect of NR1H4 pharmacological agonists in gallstone disease diabete     emerging role of NR1H4 agonists as therapeutic treatment of diabetes and certain liver diseases cardiovascular atheroma   NR1H4-NR0B2 way may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability cardiovascular     in smooth muscle cells may serve as a novel molecular target for modulating AGTR2 signalling in the vasculature diabete     activation of both NR1H4 and GPBAR1 may represent an effective therapy for diabetes digestive liver steatosis activation of both NR1H4 and GPBAR1 may represent an effective therapy for managing hepatic steatosis miscelleaneous urinary   NR1H4 and GPBAR1 agonists play an important role in preventing progression of kidney disease, atherosclerosis, and vascular calcification neurology acquired   NR1H4 agonists, such as GW4064, represent a potential therapeutic approach for multiple sclerosis (MS) which specifically targets peripheral immune cells including macrophages but not brain-resident cells, such as oligodendrocytes, astrocytes or microglia immunology infectious   may represent a therapeutic strategy for cholestasis-associated sepsis miscelleaneous vascular ischemic injury is a potential target for the prevention of atherothrombotic disease cancer digestive liver NR1H4-SOCS3 signaling may serve as a new potential target for the prevention/treatment of hepatocellular carcinoma digestive     Src-mediated NR1H4 phosphorylation is a potential therapeutic target for Bile-acid-related enterohepatic diseases

ANIMAL & CELL MODELS

mice lacking expression of Fxr in the intestine were resistant to high-fat diet (HFD)-induced obesity, insulin resistance, and nonalcoholic fatty liver disease, thus confirming that intestinal Fxr is involved in the potentiation of metabolic disease