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Overview

Hepatocyte nuclear factor 4 alpha (HNF4α, NR2A1, gene symbol HNF4A) is a highly conserved member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors [1] and an essential gene in early development as well as in the adult (Fig. 1)[2][3]. HNF4α is expressed in the adult liver, kidney, pancreas, intestine, colon and to a lesser degree in the stomach, as well as in the visceral endoderm. HNF4α is a nuclear protein that binds DNA exclusively as a homodimer [4]; it also exhibits strong homodimerization activity in the absence of DNA and cannot heterodimerize with retinoid X receptor (RXR), unlike other nuclear receptors [5][6].

HNF4α activates the expression of hundreds of genes, especially those involved in intermediary metabolism, including glucose, fatty acid, cholesterol and xenobiotic and drug metabolism (Fig.s 2, 4)[7][8].

There are two promoters (P1 and P2) that drive the expression of at least 6 different HNF4α splice variants (often referred to as isoforms) that exhibit varying levels of transactivation activity and are expressed in a temporal and spatial-specific fashion (see Fig. 3).

HNF4α was long considered an orphan receptor as the identity of its ligand was unknown. While there was some controversy in the literature about the nature of the HNF4α ligand and whether it bound in a reversible fashion [9][10][11][5], a recent report indicates that HNF4α binds a single fatty acid (linoelic acid, LA, C18:2) in a reversible fashion, and that apoHNF4α exists in physiological conditions [12]. This finding suggests that HNF4α may be a potential drug target, as are many of the other NRs.

HNF4α is at the center of a complex network of transcriptional control involving other HNFs and NRs [13][14] and has been directly linked to several human diseases including diabetes, hemophilia and hepatitis B viral infections. Mutations in the HNF4A coding region and promoter are directly linked to Maturity Onset Diabetes of the Young 1 (MODY1) [15][16] while mutations in HNF4α binding sites in the promoter regions of blood coagulation factors have been linked to certain types of hemophilia [17]. HNF4α also regulates most if not all of the apolipoprotein genes in the liver and may therefore play a role in atherosclerosis (Fig. 4). Finally, HNF4α regulates the expression of many cytochrome P450 genes (e.g., CYP3A4, CYP2D6) and Phase II enzymes and hence may play a role in drug metabolism [18]. Polymorphisms in the human HNF4A gene are increasingly being associated with altered levels of HNF4α protein and hence its target genes, resulting in altered risks of diseases such as diabetes, metabolic syndrome as well as altered drug metabolism activity [19][20][21][22].

References
  1. Sladek FM et al. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev., 4(12B):2353-65. (PMID 2279702)
  2. Chen WS et al. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev., 8(20):2466-77. (PMID 7958910)
  3. Hayhurst GP et al. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell. Biol., 21(4):1393-403. (PMID 11158324)
  4. Jiang G et al. 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)
  5. Bogan AA et al. Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha. J. Mol. Biol., 302(4):831-51. (PMID 10993727)
  6. Jiang G et al. Proposed mechanism for the stabilization of nuclear receptor DNA binding via protein dimerization. Mol. Cell. Biol., 17(11):6546-54. (PMID 9343418)
  7. Odom DT et al. Control of pancreas and liver gene expression by HNF transcription factors. Science, 303(5662):1378-81. (PMID 14988562)
  8. Waxman DJ and Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol. Pharmacol., 76(2):215-28. (PMID 19483103)
  9. Hertz R et al. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature, 392(6675):512-6. (PMID 9548258)
  10. Wisely GB et al. Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. Structure, 10(9):1225-34. (PMID 12220494)
  11. Dhe-Paganon S et al. Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand. J. Biol. Chem., 277(41):37973-6. (PMID 12193589)
  1. Yuan X et al. Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLoS ONE, 4(5):e5609. (PMID 19440305)
  2. Kyrmizi I et al. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev., 20(16):2293-305. (PMID 16912278)
  3. Tomaru Y et al. Identification of an inter-transcription factor regulatory network in human hepatoma cells by Matrix RNAi. Nucleic Acids Res., 37(4):1049-60. (PMID 19129217)
  4. Yamagata K et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature, 384(6608):458-60. (PMID 8945471)
  5. Ellard S and Colclough K. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Hum. Mutat., 27(9):854-69. (PMID 16917892)
  6. Reijnen MJ et al. Disruption of a binding site for hepatocyte nuclear factor 4 results in hemophilia B Leyden. Proc. Natl. Acad. Sci. U.S.A., 89(14):6300-3. (PMID 1631121)
  7. Gonzalez FJ. Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab. Pharmacokinet., 23(1):2-7. (PMID 18305369)
  8. Weissglas-Volkov D et al. Common hepatic nuclear factor-4alpha variants are associated with high serum lipid levels and the metabolic syndrome. Diabetes, 55(7):1970-7. (PMID 16804065)
  9. Wortham M et al. Expression of constitutive androstane receptor, hepatic nuclear factor 4 alpha, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver. Drug Metab. Dispos., 35(9):1700-10. (PMID 17576804)
  10. Aueviriyavit S et al. Hepatocyte nuclear factor 1 alpha and 4 alpha are factors involved in interindividual variability in the expression of UGT1A6 and UGT1A9 but not UGT1A1, UGT1A3 and UGT1A4 mRNA in human livers. Drug Metab. Pharmacokinet., 22(5):391-8. (PMID 17965524)
  11. Lee SS et al. Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity. Hepatology, 48(2):635-45. (PMID 18666237)
Figures
FIGURE 1 HHNF4α is highly conserved evolutionarily.
Shown are percent amino acid identity among the various functional domains of the HNF4a protein. Numbers refer to amino acid residues. DBD, DNA binding domain. LBD, ligand binding domain.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.