Hepatocyte nuclear factor-4-γ | 2A. Hepatocyte nuclear factor-4 receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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Hepatocyte nuclear factor-4-γ

Target not currently curated in GtoImmuPdb

Target id: 609

Nomenclature: Hepatocyte nuclear factor-4-γ

Systematic Nomenclature: NR2A2

Family: 2A. Hepatocyte nuclear factor-4 receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 445 8q21-q22 HNF4G hepatocyte nuclear factor 4 gamma 3
Mouse 418 3A1 Hnf4g hepatocyte nuclear factor 4 6
Rat - 2q24 Hnf4g hepatocyte nuclear factor 4
Previous and Unofficial Names
hepatocyte nuclear factor 4
Database Links
Specialist databases
NURSA Receptor 10.1621/OJDZSS39QY (Hs)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Hepatocyte nuclear factor 4-gamma -ligand binding domain
PDB Id:  1LV2
Ligand:  palmitic acid   This ligand is endogenous
Resolution:  2.7Å
Species:  Human
References:  7
Natural/Endogenous Ligands
Comments: Orphan
Agonist Comments
Fatty acids originating from bacteria were found in crystalized HNF4γ LBD. Authors showed that these fatty acids were not exchangeable without prior denaturation of the protein and suggested that fatty acids act as co-factors, rather than exchangeable ligands. Recent work on HNF4α in mammalian cells by the groups of Forman and Sladek, however, suggest that the bacterially expressed protein may not be an accurate representation of HNF4 in vivo [7].
DNA Binding
Structure:  Homodimer
HRE core sequence:  AGGTCA n AGGTCA
Response element:  DR1
DNA Binding Comments
The HNF4γ DBD is nearly identical to that of HNF4α (62/66 amino acids with the remaining four being conservative changes) and shares at least some of the same response elements with HNF4α. On the one element where HNF4α and γ were compared side-by-side, they displayed similar DNA binding affinities. Despite the fact that HNF4γ contains the same signature motif which directs dimerization in HNF4α, other groups have not found evidence of HNF4γ and HNF4α heterodimers [1-2].
Main Target Genes
Name Species Effect Technique Comments References
Apoc3 Mouse Activated Transient transfection 6
Apoa4 Mouse Activated Transient transfection, EMSA, Footprint 1,5
Tat Mouse Activated Transient transfection 6
HNF1α Human Activated Transient transfection 3
AKR1C4 Human Activated EMSA, Footprint HNF-4alpha, HNF-4gamma and HNF-1alpha regulate co-operatively the transcription of the human DD4 gene in HepG2 cells 4
Tissue Distribution Comments
HNF4γ was detected as a 6.0 kb species in endocrine pancreas, kidney, small intestine and testis, but, strikingly, not in liver and only very weakly in colon. HNF4γ is expressed only in the villus while HNF4α is expressed in the entire length of the crypt-to-villus axis. In general HNF4γ is more than 10 fold less abundant than HNF4α. It was detected in, human, mouse and rat studies [5-6].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0005450 abnormal energy expenditure PMID: 16945327 
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0003313 abnormal locomotor activation PMID: 16945327 
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0001943 abnormal respiration PMID: 16945327 
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0003064 decreased coping response PMID: 16945327 
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0003912 decreased drinking behavior PMID: 16945327 
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0003910 decreased eating behavior PMID: 16945327 
Hnf4gtm1Dgen Hnf4gtm1Dgen/Hnf4gtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1353604  MP:0001260 increased body weight PMID: 16945327 


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1. Archer A, Sauvaget D, Chauffeton V, Bouchet PE, Chambaz J, Pinçon-Raymond M, Cardot P, Ribeiro A, Lacasa M. (2005) Intestinal apolipoprotein A-IV gene transcription is controlled by two hormone-responsive elements: a role for hepatic nuclear factor-4 isoforms. Mol. Endocrinol., 19 (9): 2320-34. [PMID:15928313]

2. Bogan AA, Dallas-Yang Q, Ruse MD, Maeda Y, Jiang G, Nepomuceno L, Scanlan TS, Cohen FE, Sladek FM. (2000) Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha. J. Mol. Biol., 302 (4): 831-51. [PMID:10993727]

3. Drewes T, Senkel S, Holewa B, Ryffel GU. (1996) Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol. Cell. Biol., 16 (3): 925-31. [PMID:8622695]

4. Ozeki T, Takahashi Y, Kume T, Nakayama K, Yokoi T, Nunoya K, Hara A, Kamataki T. (2001) Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)4/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4alpha/gamma and HNF-1alpha. Biochem. J., 355 (Pt 2): 537-44. [PMID:11284743]

5. Sauvaget D, Chauffeton V, Citadelle D, Chatelet FP, Cywiner-Golenzer C, Chambaz J, Pinçon-Raymond M, Cardot P, Le Beyec J, Ribeiro A. (2002) Restriction of apolipoprotein A-IV gene expression to the intestine villus depends on a hormone-responsive element and parallels differential expression of the hepatic nuclear factor 4alpha and gamma isoforms. J. Biol. Chem., 277 (37): 34540-8. [PMID:12105231]

6. Taraviras S, Mantamadiotis T, Dong-Si T, Mincheva A, Lichter P, Drewes T, Ryffel GU, Monaghan AP, Schütz G. (2000) Primary structure, chromosomal mapping, expression and transcriptional activity of murine hepatocyte nuclear factor 4gamma. Biochim. Biophys. Acta, 1490 (1-2): 21-32. [PMID:10786614]

7. Wisely GB, Miller AB, Davis RG, Thornquest AD, Johnson R, Spitzer T, Sefler A, Shearer B, Moore JT, Miller AB, Willson TM, Williams SP. (2002) Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. Structure, 10 (9): 1225-34. [PMID:12220494]


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How to cite this page

Frances M. Sladek.
2A. Hepatocyte nuclear factor-4 receptors: Hepatocyte nuclear factor-4-γ. Last modified on 18/08/2014. Accessed on 24/04/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=609.