2A. Hepatocyte nuclear factor-4 receptors | Nuclear hormone receptors

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2A. Hepatocyte nuclear factor-4 receptors

2A. Hepatocyte nuclear factor-4 receptors C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [1-2]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [10]. HNF4γ has yet to be paired with an endogenous ligand.

Receptors

Hepatocyte nuclear factor-4-α / NR2A1 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

608

Nomenclature

Hepatocyte nuclear factor-4-α

Systematic nomenclature

NR2A1

Previous and unofficial names

Genes

HNF4A (Hs), Hnf4a (Mm), Hnf4a (Rn)

Ensembl ID

ENSG00000101076 (Hs), ENSMUSG00000017950 (Mm), ENSRNOG00000008895 (Rn)

UniProtKB AC

P41235 (Hs), P49698 (Mm), P22449 (Rn)

Endogenous agonists

linoleic acid (Selective) [10]

Agonists

benfluorex [6]

alverine [6]

Selective agonists

HNF4α inhibitor

Selective antagonists

BI6015 [4]

Comment

HNF4α was purified originally from liver but is also found in other tissues including the kidney, intestines, pancreas and stomach [7-8]. Its expression is driven by two promoters, leading to several isoform variants, the abundance of which vary between the tissues where HNF4 is expressed [5]. HNF4α has constitutive transactivation activity [10] and binds DNA as a homodimer [3].

Hepatocyte nuclear factor-4-γ / NR2A2 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id	609
Nomenclature	Hepatocyte nuclear factor-4-γ
Systematic nomenclature	NR2A2
Previous and unofficial names	hepatocyte nuclear factor 4
Genes	HNF4G (Hs), Hnf4g (Mm), Hnf4g (Rn)
Ensembl ID	ENSG00000164749 (Hs), ENSMUSG00000017688 (Mm), ENSRNOG00000008971 (Rn)
UniProtKB AC	Q14541 (Hs), Q9WUU6 (Mm)
Comment	HNF4γ is structurally very similar to HNF4α although its expression is restricted to the intestinal tract. HNF4γ has two known isoforms, though it is unknown if this is due to alternative promoter usage or alternative splicing. The two HNF4 receptors can bind DNA as heterodimers as well as homodimers [9].

References

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1. Alexander SPH, Cidlowski JA, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ et al.. (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Nuclear hormone receptors. Br J Pharmacol, 176 Suppl 1: S229-S246. [PMID:31710718]

2. Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev, 58 (4): 798-836. [PMID:17132856]

3. Jiang G, Nepomuceno L, Hopkins K, Sladek FM. (1995) Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. Mol Cell Biol, 15 (9): 5131-43. [PMID:7651430]

4. Kiselyuk A, Lee SH, Farber-Katz S, Zhang M, Athavankar S, Cohen T, Pinkerton AB, Ye M, Bushway P, Richardson AD et al.. (2012) HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chem Biol, 19 (7): 806-18. [PMID:22840769]

5. Ko HL, Zhuo Z, Ren EC. (2019) HNF4α Combinatorial Isoform Heterodimers Activate Distinct Gene Targets that Differ from Their Corresponding Homodimers. Cell Rep, 26 (10): 2549-2557.e3. [PMID:30840880]

6. Lee SH, Athavankar S, Cohen T, Piran R, Kiselyuk A, Levine F. (2013) Identification of alverine and benfluorex as HNF4α activators. ACS Chem Biol, 8 (8): 1730-6. [PMID:23675775]

7. Radi SH, Vemuri K, Martinez-Lomeli J, Sladek FM. (2023) HNF4α isoforms: the fraternal twin master regulators of liver function. Front Endocrinol (Lausanne), 14: 1226173. [PMID:37600688]

8. Sladek FM, Zhong WM, Lai E, Darnell JE. (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev, 4 (12B): 2353-65. [PMID:2279702]

9. Vemuri K, Radi SH, Sladek FM, Verzi MP. (2023) Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine. Front Endocrinol (Lausanne), 14: 1232569. [PMID:37635981]

10. Yuan X, Ta TC, Lin M, Evans JR, Dong Y, Bolotin E, Sherman MA, Forman BM, Sladek FM. (2009) Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLoS ONE, 4 (5): e5609. [PMID:19440305]

NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation (select format):

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Cidlowski JA, Gibb AJ, Kelly E, Mathie AA, Peach CJ, Veale EL, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Nuclear hormone receptors. Br J Pharmacol. 182: S242-S258.