TABLE 8

HNFα

Receptor nomenclature NR2A1
Receptor code 4.10.1:OR:2:A1
Other names HNF-4, MODY1, TCF14
Molecular information Hs: 465aa, P41235, chr. 20q131,2
Rn: 465aa, P22449, chr. 3q423,4
Mm: 465aa, P49698, chr. 2 H35,6
DNA binding
   Structure Homodimer
   HRE core sequence AGGTCA n AGGTCA (DR-1, DR-2)4,7
Partners HIF (physical, functional): transactivation8–10; HNF-1A (physical, functional): transactivation11–13; COUP-TFI, COUP-TFII (functional): transactivation and competition for DNA binding14–16; SHP (physical, functional): transactivation17,18; SMADs (physical, functional): transactivation19,20
Agonists
Antagonists
Coactivators NCOA1, NCOA2, CREBBP, PPARGC1A, PPARGC1B, PPARBP21–27
Corepressors NCOR228
Biologically important isoforms HNF-4α1 {Hs, Mm, Rn}: main isoform1,4,5; HNF-4α2 (variant B){Hs, Mm, Rn}: contains an additional 10 amino acids in the F domain and is the most prominent form in the liver and kidney1,5,21; HNF-4α3 (variant C) {Hs, Mm}: displays reduced transcriptional activity and liver expression compared with isoforms 1 and 229; HNF-4α4 {Hs, Mm}: this variant has an insertion in the AF-1 of HNF-4α130; HNF-4α7 and HNF-4α8 {Hs, Mm, Rn}: transcribed from a different promoter and have a different N terminus from the isoforms above but the same F domain as HNF-4α1 and HNF-4α231–34
Tissue distribution Developmental: primary endoderm, liver, kidney, pancreas, stomach, intestine; adult: HNFα-1 and -2–liver (hepatocytes), kidney, small intestine and colon but not in the pancreas; HNFα-3 and -4–liver; HNFα-7–pancreas, adult liver, small intestine, colon, stomach but not in the liver {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]4,35–37
Functional assays Measurement of receptor activity using CAT and luciferase reporter genes in HeLa, HepG2, Hep3B, Saos2, Caco-2, and HEK 293 cells {Hs}4,28,38; ectopic overexpression of HNF-4α in fibroblasts induces a mesenchymal-to-epithelial transition, indicating that HNF-4α is a dominant regulator of the epithelial phenotype {Mm}39
Main target genes Activated: ApoC3 {Hs, Mm, Rn},4,40,41 ApoB {Hs},41,42 HNF1A {Hs, Mm, Rn},41,43,44 PEPCK {Hs, Mm, Rn},41,45 CYP3A4 {Hs}34,46,47
Mutant phenotype Targeted disruption of the HNF-4α gene results in embryonic lethality; the embryos initiate but do not complete gastrulation in the absence of HNF-4α {Mm} [knockout]48,49; adult mice lacking hepatic HNF-4α expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations {Mm} [knockout]39,50,51; mice lacking HNF-4α in pancreatic β cells have hyperinsulinemia and, paradoxically, impaired glucose tolerance, as well as impaired glucose-stimulated insulin secretion and dysfunction of the KATP channel activity {Mm} [conditional knockout]52,53
Human disease Early-onset type 2 diabetes: due to the three SNPs (Asp126→Tyr, Asp126→His, Arg154→Gln)54; late-onset type 2 diabetes: due to missense mutations in the LBD and F domain and 13 SNPs in the P2 promoter55–58; MODY1: caused by mutations in several different human populations affecting either the DBD or LBD32,59–63; factor VII deficiency: caused by mutations in the HNF-4α-binding site in the blood coagulation factor VII gene64; hemophilia B Leyden: caused by mutations in the HNF-4α-binding site in the blood coagulation factor IX gene65–67

  • aa, amino acids; chr., chromosome; HRE, hormone response element; HIF, hypoxia-inducing factor; CREBBP, cAMP response element-binding protein binding protein; PPARGC, PPAR coactivator gene; PPARBP, PPAR binding protein; SNP, single-nucleotide polymorphism; MODY1, maturity-onset diabetes of the young type 1; CAT, chloroamphenicol acetyl transferase; PEPCK, phosphoenolpyruvate carboxykinase

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  • ↵2. Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, and Moschonas NK (1997) Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17. Hum Genet 99: 233-236

  • ↵3. Hata S, Tsukamoto T, and Osumi T (1992) A novel isoform of rat hepatocyte nuclear factor 4 (HNF-4). Biochim Biophys Acta 1131: 211-213

  • ↵4. Sladek FM, Zhong WM, Lai E, and Darnell JE Jr (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4: 2353-2365

  • ↵5. Hata S, Inoue T, Kosuga K, Nakashima T, Tsukamoto T, and Osumi T (1995) Identification of two splice isoforms of mRNA for mouse hepatocyte nuclear factor 4 (HNF-4). Biochim Biophys Acta 1260: 55-61

  • ↵6. Avraham KB, Prezioso VR, Chen WS, Lai E, Sladek FM, Zhong W, Darnell JE Jr, Jenkins NA, and Copeland NG (1992) Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3α, HNF-3β, HNF-3γ, and HNF-4. Genomics 13: 264-268

  • ↵7. Jiang G and Sladek FM (1997) The DNA binding domain of hepatocyte nuclear factor 4 mediates cooperative, specific binding to DNA and heterodimerization with the retinoid X receptor α. J Biol Chem 272: 1218-1225

  • ↵8. Galson DL, Tsuchiya T, Tendler DS, Huang LE, Ren Y, Ogura T, and Bunn HF (1995) The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol 15: 2135-2144

  • ↵9. Zhang W, Tsuchiya T, and Yasukochi Y (1999) Transitional change in interaction between HIF-1 and HNF-4 in response to hypoxia. J Hum Genet 44: 293-299

  • ↵10. Tsuchiya T, Kominato Y, and Ueda M (2002) Human hypoxic signal transduction through a signature motif in hepatocyte nuclear factor 4. J Biochem (Tokyo) 132: 37-44

  • ↵11. Ktistaki E and Talianidis I (1997) Modulation of hepatic gene expression by hepatocyte nuclear factor 1. Science (Wash DC) 277: 109-112

  • ↵12. Hu C and Perlmutter DH (1999) Regulation of α 1-antitrypsin gene expression in human intestinal epithelial cell line caco-2 by HNF-1α and HNF-4. Am J Physiol 276: G1181-G1194

  • ↵13. Rowley CW, Staloch LJ, Divine JK, McCaul SP, and Simon TC (2006) Mechanisms of mutual functional interactions between HNF-4α and HNF-1α revealed by mutations that cause maturity onset diabetes of the young. Am J Physiol 290: G466-G475

  • ↵14. Mietus-Snyder M, Sladek FM, Ginsburg GS, Kuo CF, Ladias JA, Darnell JE Jr, and Karathanasis SK (1992) Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol 12: 1708-1718

  • ↵15. Ktistaki E and Talianidis I (1997) Chicken ovalbumin upstream promoter transcription factors act as auxiliary cofactors for hepatocyte nuclear factor 4 and enhance hepatic gene expression. Mol Cell Biol 17: 2790-2797

  • ↵16. Sugiyama T, Wang JC, Scott DK, and Granner DK (2000) Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI): definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene. J Biol Chem 275: 3446-3454

  • ↵17. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, and Moore DD (2000) The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol 20: 187-195

  • ↵18. Shimamoto Y, Ishida J, Yamagata K, Saito T, Kato H, Matsuoka T, Hirota K, Daitoku H, Nangaku M, Yamagata K, et al. (2004) Inhibitory effect of the small heterodimer partner on hepatocyte nuclear factor-4 mediates bile acid-induced repression of the human angiotensinogen gene. J Biol Chem 279: 7770-7776

  • ↵19. Kardassis D, Pardali K, and Zannis VI (2000) SMAD proteins transactivate the human ApoCIII promoter by interacting physically and functionally with hepatocyte nuclear factor 4. J Biol Chem 275: 41405-41414

  • ↵20. Chou WC, Prokova V, Shiraishi K, Valcourt U, Moustakas A, Hadzopoulou-Cladaras M, Zannis VI, and Kardassis D (2003) Mechanism of a transcriptional cross talk between transforming growth factor-β-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4. Mol Biol Cell 14: 1279-1294

  • ↵21. Sladek FM, Ruse MD Jr, Nepomuceno L, Huang SM, and Stallcup MR (1999) Modulation of transcriptional activation and coactivator interaction by a splicing variation in the F domain of nuclear receptor hepatocyte nuclear factor 4α 1. Mol Cell Biol 19: 6509-6522

  • ↵22. Wang JC, Stafford JM, and Granner DK (1998) SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. J Biol Chem 273: 30847-30850

  • ↵23. Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, and Fukamizu A (1997) Functional association between CBP and HNF4 in trans-activation. Biochem Biophys Res Commun 241: 664-669

  • ↵24. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, et al. (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature (Lond) 413: 131-138

  • ↵25. Lin J, Puigserver P, Donovan J, Tarr P, and Spiegelman BM (2002) Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 277: 1645-1648

  • ↵26. Maeda Y, Rachez C, Hawel L 3rd, Byus CV, Freedman LP, and Sladek FM (2002) Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205. Mol Endocrinol 16: 1502-1510

  • ↵27. Malik S, Wallberg AE, Kang YK, and Roeder RG (2002) TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4. Mol Cell Biol 22: 5626-5637

  • ↵28. use MD Jr, Privalsky ML, and Sladek FM (2002) Competitive cofactor recruitment by orphan receptor hepatocyte nuclear factor 4α 1: modulation by the F domain. Mol Cell Biol 22: 1626-1638

  • ↵29. Kritis AA, Argyrokastritis A, Moschonas NK, Power S, Katrakili N, Zannis VI, Cereghini S, and Talianidis I (1996) Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4. Gene 173: 275-280

  • ↵30. Drewes T, Senkel S, Holewa B, and Ryffel GU (1996) Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol 16: 925-931

  • ↵31. Nakhei H, Lingott A, Lemm I, and Ryffel GU (1998) An alternative splice variant of the tissue specific transcription factor HNF4α predominates in undifferentiated murine cell types. Nucleic Acids Res 26: 497-504

  • ↵32. Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, Roosen S, Lingott-Frieg A, Tack CJ, Ellard S, Ryffel GU, et al. (2001) A distant upstream promoter of the HNF-4α gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 10: 2089-2097

  • ↵33. Boj SF, Parrizas M, Maestro MA, and Ferrer J (2001) A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA 98: 14481-14486

  • ↵34. Sladek FM and Seidel SD (2001) Hepatocyte nuclear factor 4α, in Nuclear Receptors and Genetic Diseases (Burris TP and ERB McCabe ERB eds) pp 309-361, Academic Press, London

  • ↵35. Duncan SA, Manova K, Chen WS, Hoodless P, Weinstein DC, Bachvarova RF, and Darnell JE Jr (1994) Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci USA 91: 7598-7602

  • ↵36. Tanaka T, Jiang S, Hotta H, Takano K, Iwanari H, Sumi K, Daigo K, Ohashi R, Sugai M, Ikegame C, et al. (2006) Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4α in the pathogenesis of human cancer. J Pathol 208: 662-672

  • ↵37. Eeckhoute J, Moerman E, Bouckenooghe T, Lukoviak B, Pattou F, Formstecher P, Kerr-Conte J, Vandewalle B, and Laine B (2003) Hepatocyte nuclear factor 4 α isoforms originated from the P1 promoter are expressed in human pancreatic β -cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms. Endocrinology 144: 1686-1694

  • ↵38. Maeda Y, Seidel SD, Wei G, Liu X, and Sladek FM (2002) Repression of hepatocyte nuclear factor 4α tumor suppressor p53: involvement of the ligand-binding domain and histone deacetylase activity. Mol Endocrinol 16: 402-410

  • ↵39. Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, and Duncan SA (2003) Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34: 292-296

  • ↵40. Kardassis D, Tzameli I, Hadzopoulou-Cladaras M, Talianidis I, and Zannis V (1997) Distal apolipoprotein C-III regulatory elements F to J act as a general modular enhancer for proximal promoters that contain hormone response elements: synergism between hepatic nuclear factor-4 molecules bound to the proximal promoter and distal enhancer sites. Arterioscler Thromb Vasc Biol 17: 222-232

  • ↵41. Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, et al. (2004) Control of pancreas and liver gene expression by HNF transcription factors. Science (Wash DC) 303: 1378-1381

  • ↵42. Metzger S, Halaas JL, Breslow JL, and Sladek FM (1993) Orphan receptor HNF-4 and bZip protein C/EBPα bind to overlapping regions of the apolipoprotein B gene promoter and synergistically activate transcription. J Biol Chem 268: 16831-16838

  • ↵43. Kuo CJ, Conley PB, Chen L, Sladek FM, Darnell JE Jr, and Crabtree GR (1992) A transcriptional hierarchy involved in mammalian cell-type specification. Nature (Lond) 355: 457-461

  • ↵44. Gragnoli C, Lindner T, Cockburn BN, Kaisaki PJ, Gragnoli F, Marozzi G, and Bell GI (1997) Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 α binding site in the promoter of the hepatocyte nuclear factor-1 α gene. Diabetes 46: 1648-1651

  • ↵45. Hall RK, Sladek FM, and Granner DK (1995) The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Proc Natl Acad Sci USA 92: 412-416

  • ↵46. Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, et al. (2003) The orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9: 220-224

  • ↵47. Akiyama TE and Gonzalez FJ (2003) Regulation of P450 genes by liver-enriched transcription factors and nuclear receptors. Biochim Biophys Acta 1619: 223-234

  • ↵48. Chen WS, Manova K, Weinstein DC, Duncan SA, Plump AS, Prezioso VR, Bachvarova RF, and Darnell JE Jr (1994) 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: 2466-2477

  • ↵49. Duncan SA, Nagy A, and Chan W (1997) Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(–/–) embryos. Development 124: 279-287

  • ↵50. Hayhurst GP, Lee YH, Lambert G, Ward JM, and Gonzalez FJ (2001) Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21: 1393-1403

  • ↵51. Parviz F, Li J, Kaestner KH, and Duncan SA (2002) Generation of a conditionally null allele of hnf4α. Genesis 32: 130-133

  • ↵52. Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, Nammo T, Yoneda K, Inoue Y, Sladek FM, et al. (2006) Hepatocyte nuclear factor-4α is essential for glucose-stimulated insulin secretion by pancreatic β-cells. J Biol Chem 281: 5246-5257

  • ↵53. Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, and Kaestner KH (2005) The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. J Clin Investig 115: 1006-1015

  • ↵54. Aguilar-Salinas CA, Reyes-Rodriguez E, Ordonez-Sanchez ML, Torres MA, Ramirez-Jimenez S, Dominguez-Lopez A, Martinez-Francois JR, Velasco-Perez ML, Alpizar M, Garcia-Garcia E, et al. (2001) Early-onset type 2 diabetes: metabolic and genetic characterization in the Mexican population. J Clin Endocrinol Metab 86: 220-226

  • ↵55. Gupta RK and Kaestner KH (2004) HNF-4α : from MODY to late-onset type 2 diabetes. Trends Mol Med 10: 521-524

  • ↵56. Hani EH, Suaud L, Boutin P, Chevre JC, Durand E, Philippi A, Demenais F, VionnettaJ, Furuta H, Velho G, et al. (1998) A missense mutation in hepatocyte nuclear factor-4 α, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Investig 101: 521-526

  • ↵57. Muller YL, Infante AM, Hanson RL, Love-Gregory L, Knowler W, Bogardus C, and Baier LJ (2005) Variants in hepatocyte nuclear factor 4 α are modestly associated with type 2 diabetes in Pima Indians. Diabetes 54: 3035-3039

  • ↵58. Price JA, Fossey SC, Sale MM, Brewer CS, Freedman BI, Wuerth JP, and Bowden DW (2000) Analysis of the HNF4α gene in Caucasian type II diabetic nephropathic patients. Diabetologia 43: 364-372

  • ↵59. Ryffel GU (2001) Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF) 1 and HNF4 families: functional and pathological consequences. J Mol Endocrinol 27: 11-29

  • ↵60. Barrio R, Bellanne-Chantelot C, Moreno JC, Morel V, Calle H, Alonso M, and Mustieles C (2002) Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab 87: 2532-2539

  • ↵61. Pruhova S, Ek J, Lebl J, Sumnik Z, Saudek F, Andel M, Pedersen O, and Hansen T (2003) Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4α, GCK and HNF-1α. Diabetologia 46: 291-295

  • ↵62. Monney CT, Kaltenrieder V, Cousin P, Bonny C, and Schorderet DF (2002) Large family with maturity-onset diabetes of the young and a novel V121I mutation in HNF4A. Hum Mutat 20: 230-231

  • ↵63. Oxombre B, Moerman E, Eeckhoute J, Formstecher P, and Laine B (2002) Mutations in hepatocyte nuclear factor 4α (HNF4α) gene associated with diabetes result in greater loss of HNF4α function in pancreatic β -cells than in nonpancreatic β -cells and in reduced activation of the apolipoprotein CIII promoter in hepatic cells. J Mol Med 80: 423-430

  • ↵64. Arbini AA, Pollak ES, Bayleran JK, High KA, and Bauer KA (1997) Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter. Blood 89: 176-182

  • ↵65. Reijnen MJ, Sladek FM, Bertina RM, and Reitsma PH (1992) Disruption of a binding site for hepatocyte nuclear factor 4 results in hemophilia B Leyden. Proc Natl Acad Sci USA 89: 6300-6303

  • ↵66. Naka H and Brownlee GG (1996) Transcriptional regulation of the human factor IX promoter by the orphan receptor superfamily factor, HNF4, ARP1 and COUP/Ear3. Br J Haematol 92: 231-240

  • ↵67. Morgan GE, Rowley G, Green PM, Chisholm M, Giannelli F, and Brownlee GG (1997) Further evidence for the importance of an androgen response element in the factor IX promoter. Br J Haematol 98: 79-85