Fish Physiology and Biochemistry

, Volume 44, Issue 3, pp 805–815 | Cite as

Hnf4α is involved in the regulation of vertebrate LC-PUFA biosynthesis: insights into the regulatory role of Hnf4α on expression of liver fatty acyl desaturases in the marine teleost Siganus canaliculatus

  • Shuqi Wang
  • Junliang Chen
  • Danli Jiang
  • Qinghao Zhang
  • Cuihong You
  • Douglas R. Tocher
  • Óscar Monroig
  • Yewei Dong
  • Yuanyou Li
Article

Abstract

Long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis is an important metabolic pathway in vertebrates, especially fish, considering they are the major source of n-3 LC-PUFA in the human diet. However, most fish have only limited capability for biosynthesis of LC-PUFA. The rabbitfish (Siganus canaliculatus) is able to synthesize LC-PUFA as it has all the key enzyme activities required including Δ6Δ5 Fads2, Δ4 Fads2, Elovl5, and Elovl4. We previously reported a direct interaction between the transcription factor Hnf4α and the promoter regions of Δ4 and Δ6Δ5 Fads2, which suggested that Hnf4α was involved in the transcriptional regulation of fads2 in rabbitfish. For functionally investigating it further, a full-length cDNA of 1736-bp-encoding rabbitfish Hnf4α with 454 amino acids was cloned, which was highly expressed in intestine, followed by liver and eyes. Similar to the expression characteristics of its target genes Δ4 and Δ6Δ5 fads2, levels of hnf4α mRNA in liver and eyes were higher in fish reared at low salinity than those reared in high salinity. After the rabbitfish primary hepatocytes were, respectively, incubated with alverine, benfluorex or BI6015, which were anticipated agonists or antagonist for Hnf4α, the mRNA level of Δ6Δ5 and Δ4 fads2 displayed a similar change tendency with that of hnf4α mRNA. Furthermore, when the mRNA level of hhf4α was knocked down using siRNA, the expression of Δ6Δ5 and Δ4 fads2 also decreased. Together, these data suggest that Hnf4α is involved in the transcriptional regulation of LC-PUFA biosynthesis, specifically, by targeting Δ4 and Δ6Δ5 fads2 in rabbitfish.

Keywords

Fatty acyl desaturase LC-PUFA biosynthesis Hnf4α Transcriptional regulation mechanism Rabbitfish Siganus canaliculatus 

Notes

Acknowledgements

This work was financially supported by the Major International Joint Research Project from National Natural Science Foundation of China (NSFC) (31110103913), China Agriculture Research System (CARS-47), and Innovation and Strong School Projects in Guangdong Province (2015KCXTD017, 2016KTSCX037).

References

  1. Bailly A, Briançon N, Weiss MC (2009) Characterization of glucocorticoid receptor and hepatocyte nuclear factor 4α (HNF4α) binding to the hnf4α gene in the liver. Biochimie 91(9):1095–1103.  https://doi.org/10.1016/j.biochi.2009.06.009 CrossRefPubMedGoogle Scholar
  2. Bailly A, Torres-Padilla ME, Tinel AP, Weiss MC (2001) An enhancer element 6 kb upstream of the mouse HNF4α1 promoter is activated by glucocorticoids and liver-enriched transcription factors. Nucleic Acids Res 29(17):3495–3505.  https://doi.org/10.1093/nar/29.17.3495 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Brock TJ, Watts JL (2006) Genetic regulation of unsaturated fatty acid composition in C. elegans Google Scholar
  4. Calder PC (2013) N-3 fatty acids, inflammation and immunity: new mechanisms to explain old actions. Proc Nutr Soc 72(03):326–336.  https://doi.org/10.1017/S0029665113001031 CrossRefPubMedGoogle Scholar
  5. Campoy C, Escolano-Margarit MV, Anjos T, Szajewska H, Uauy R (2012) Omega 3 fatty acids on child growth, visual acuity and neurodevelopment. Br J Nutr 107(S2):S85–S106.  https://doi.org/10.1017/S0007114512001493 CrossRefPubMedGoogle Scholar
  6. Castro LFC, Tocher DR, Monroig O (2016) Long-chain polyunsaturated fatty acid biosynthesis in chordates: Insights into the evolution of Fads and Elovl gene repertoire. Progress in lipid research 62:25–40.  https://doi.org/10.1016/j.plipres.2016.01.001
  7. Delgado-Lista J, Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F (2012) Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br J Nutr 107(S2):S201–S213.  https://doi.org/10.1017/S0007114512001596 CrossRefPubMedGoogle Scholar
  8. Dong Y, Wang S, Chen J, Zhang Q, Liu Y, You C, Monroig Ó, Tocher DR, Li Y (2016) Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor of vertebrate fatty acyl desaturase gene as identified in marine teleost Siganus Canaliculatus. PLoS One 11(7):e0160361.  https://doi.org/10.1371/journal.pone.0160361 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fonseca-Madrigal J, Navarro JC, Hontoria F, Tocher DR, Martínez-Palacios CA, Monroig Ó (2014) Diversification of substrate specificities in teleostei Fads2: characterization of Δ4 and Δ6Δ5 desaturases of Chirostoma estor. Journal of lipid research 55:1408–1419.  https://doi.org/10.1194/jlr.M049791
  10. Fonseca-Madrigal J, Pineda-Delgado D, Martínez-Palacios C, Rodríguez C, Tocher DR (2012) Effect of salinity on the biosynthesis of n-3 long-chain polyunsaturated fatty acids in silverside Chirostoma estor. Fish Physiol Biochem 38(4):1047–1057.  https://doi.org/10.1007/s10695-011-9589-6 CrossRefPubMedGoogle Scholar
  11. Gil A, Serra-Majem L, Calder PC, Uauy R (2012) Systematic reviews of the role of omega-3 fatty acids in the prevention and treatment of disease. Br J Nutr 107(S2):S1–S2.  https://doi.org/10.1017/S0007114512001420 CrossRefPubMedGoogle Scholar
  12. Hatzis P, Talianidis I (2001) Regulatory mechanisms controlling human hepatocyte nuclear factor 4α gene expression. Mol Cell Biol 21(21):7320–7330.  https://doi.org/10.1128/MCB.21.21.7320-7330.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hayhurst GP, Lee Y-H, Lambert G, Ward JM, 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(4):1393–1403.  https://doi.org/10.1128/MCB.21.4.1393-1403.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Kiselyuk A, Lee S-H, Farber-Katz S, Zhang M, Athavankar S, Cohen T, Pinkerton Anthony B, Ye M, Bushway P, Richardson Adam D, Hostetler Heather A, Rodriguez-Lee M, Huang L, Spangler B, Smith L, Higginbotham J, Cashman J, Freeze H, Itkin-Ansari P, Dawson Marcia I, Schroeder F, Cang Y, Mercola M, Levine F (2012) HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chem Biol 19(7):806–818.  https://doi.org/10.1016/j.chembiol.2012.05.014 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Konstandi M, Shah YM, Matsubara T, Gonzalez FJ (2013) Role of PPARα and HNF4α in stress-mediated alterations in lipid homeostasis. PLoS One 8(8):e70675.  https://doi.org/10.1371/journal.pone.0070675 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kumar S, Stecher G, Tamura K (2016) MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol 33(7):1870–1874.  https://doi.org/10.1093/molbev/msw054 CrossRefPubMedGoogle Scholar
  17. Lee S-H, Athavankar S, Cohen T, Piran R, Kiselyuk A, Levine F (2013) Identification of alverine and benfluorex as HNF4α activators. ACS Chem Biol 8(8):1730–1736.  https://doi.org/10.1021/cb4000986 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Li J, Ning G, Duncan SA (2000) Mammalian hepatocyte differentiation requires the transcription factor HNF-4α. Genes Dev 14(4):464–474PubMedPubMedCentralGoogle Scholar
  19. Li Y, Hu C, Zheng Y, Xia X, Xu W, Wang S, Chen W, Sun Z, Huang J (2008) The effects of dietary fatty acids on liver fatty acid composition and Δ6-desaturase expression differ with ambient salinities in Siganus canaliculatus. Comp Biochem Physiol B: Biochem Mol Biol 151(2):183–190.  https://doi.org/10.1016/j.cbpb.2008.06.013 CrossRefGoogle Scholar
  20. Li Y, Monroig O, Zhang L, Wang S, Zheng X, Dick JR, You C, Tocher DR (2010) Vertebrate fatty acyl desaturase with Δ4 activity. Proc Natl Acad Sci 107(39):16840–16845.  https://doi.org/10.1073/pnas.1008429107 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Liang B, Ferguson K, Kadyk L, Watts JL (2010) The role of nuclear receptor NHR-64 in fat storage regulation in Caenorhabditis elegans. PLoS One 5(3):e9869.  https://doi.org/10.1371/journal.pone.0009869 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25(4):402–408.  https://doi.org/10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  23. Marcil V, Seidman E, Sinnett D, Boudreau F, Gendron F-P, Beaulieu J-F, Ménard D, Precourt L-P, Amre D, Levy E (2010) Modification in oxidative stress, inflammation, and lipoprotein assembly in response to hepatocyte nuclear factor 4α knockdown in intestinal epithelial cells. J Biol Chem 285(52):40448–40460.  https://doi.org/10.1074/jbc.M110.155358 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Martinez-Jimenez CP, Kyrmizi I, Cardot P, Gonzalez FJ, Talianidis I (2010) Hepatocyte nuclear factor 4α coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol 30(3):565–577.  https://doi.org/10.1128/MCB.00927-09 CrossRefPubMedGoogle Scholar
  25. Monroig Ó, Wang S, Zhang L, You C, Tocher DR, Li Y (2012) Elongation of long-chain fatty acids in rabbitfish Siganus canaliculatus: Cloning, functional characterisation and tissue distribution of Elovl5-and Elovl4-like elongases. Aquaculture 350:63–70.  https://doi.org/10.1016/j.aquaculture.2012.04.017
  26. Nakshatri H, Bhat-Nakshatri P (1998) Multiple parameters determine the specificity of transcriptional response by nuclear receptors HNF-4, ARP-1, PPAR, RAR and RXR through common response elements. Nucleic Acids Res 26(10):2491–2499.  https://doi.org/10.1093/nar/26.10.2491 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Nicolas-Frances V, Dasari VK, Abruzzi E, Osumi T, Latruffe N (2000) The peroxisome proliferator response element (PPRE) present at positions −681/−669 in the rat liver 3-ketoacyl-CoA thiolase B gene functionally interacts differently with PPARα and HNF-4. Biochem Biophys Res Commun 269(2):347–351.  https://doi.org/10.1006/bbrc.2000.2249 CrossRefPubMedGoogle Scholar
  28. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM (2003) Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci U S A 100(7):4012–4017.  https://doi.org/10.1073/pnas.0730870100 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Robinson-Rechavi M, Maina CV, Gissendanner CR, Laudet V, Sluder A (2005) Explosive lineage-specific expansion of the orphan nuclear receptor HNF4 in nematodes. J Mol Evol 60(5):577–586.  https://doi.org/10.1007/s00239-004-0175-8 CrossRefPubMedGoogle Scholar
  30. Salgado MC, Metón I, Anemaet IG, González JD, Fernández F, Baanante IV (2012) Hepatocyte nuclear factor 4α transactivates the mitochondrial alanine aminotransferase gene in the kidney of Sparus aurata. Mar Biotechnol 14(1):46–62.  https://doi.org/10.1007/s10126-011-9386-3 CrossRefPubMedGoogle Scholar
  31. Sargent JR, Tocher DR, Bell JG (2002) The lipids. Fish nutrition 3:181–257Google Scholar
  32. Sarker MA-A, Yamamoto Y, Haga Y, Sarker MSA, Miwa M, Yoshizaki G, Satoh S (2011) Influences of low salinity and dietary fatty acids on fatty acid composition and fatty acid desaturase and elongase expression in red sea bream Pagrus major. Fish Sci 77(3):385–396.  https://doi.org/10.1007/s12562-011-0342-y CrossRefGoogle Scholar
  33. Sladek FM, Zhong W, Lai E, Darnell J (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4(12b):2353–2365.  https://doi.org/10.1101/gad.4.12b.2353 CrossRefPubMedGoogle Scholar
  34. Tang C, Cho HP, Nakamura MT, Clarke SD (2003) Regulation of human Δ-6 desaturase gene transcription identification of a functional direct repeat-1 element. Journal of Lipid Research 44:686–695.  https://doi.org/10.1194/jlr.M049791
  35. Taraviras S, Monaghan AP, Schütz G, Kelsey G (1994) Characterization of the mouse HNF-4 gene and its expression during mouse embryogenesis. Mech Dev 48(2):67–79.  https://doi.org/10.1016/0925-4773(94)90017-5 CrossRefPubMedGoogle Scholar
  36. Tocher DR (2010) Fatty acid requirements in ontogeny of marine and freshwater fish. Aquac Res 41(5):717–732.  https://doi.org/10.1111/j.1365-2109.2008.02150.x CrossRefGoogle Scholar
  37. Tocher DR, Glencross BD (2015) Lipids and fatty acids, dietary nutrients, additives, and fish health. John Wiley & Sons, Inc, 47–94.  https://doi.org/10.1002/9781119005568.ch3
  38. Tur J, Bibiloni M, Sureda A, Pons A (2012) Dietary sources of omega 3 fatty acids: public health risks and benefits. Br J Nutr 107(S2):S23–S52.  https://doi.org/10.1017/S0007114512001456 CrossRefPubMedGoogle Scholar
  39. Winrow C, Marcus S, Miyata K, Zhang B, Capone J, Rachubinski R (1993) Transactivation of the peroxisome proliferator-activated receptor is differentially modulated by hepatocyte nuclear factor-4. Gene Expr 4:53–62Google Scholar
  40. Xie D, Wang S, You C, Chen F, Tocher DR, Li Y (2015) Characteristics of LC-PUFA biosynthesis in marine herbivorous teleost Siganus canaliculatus under different ambient salinities. Aquac Nutr 21(5):541–551.  https://doi.org/10.1111/anu.12178 CrossRefGoogle Scholar
  41. Xu S, Wang S, Zhang L, You C, Li Y (2012) Effects of replacement of dietary fish oil with soybean oil on growth performance and tissue fatty acid composition in marine herbivorous teleost Siganus canaliculatus. Aquac Res 43(9):1276–1286.  https://doi.org/10.1111/j.1365-2109.2011.02931.x CrossRefGoogle Scholar
  42. Yin L, Ma H, Ge X, Edwards PA, Zhang Y (2011) Hepatic hepatocyte nuclear factor 4α is essential for maintaining triglyceride and cholesterol homeostasis. Arterioscler Thromb Vasc Biol 31(2):328–336.  https://doi.org/10.1161/ATVBAHA.110.217828 CrossRefPubMedGoogle Scholar
  43. Zhang Q, Xie D, Wang S, You C, Monroig Ó, Tocher DR, Li Y (2014) miR-17 is involved in the regulation of LC-PUFA biosynthesis in vertebrates: effects on liver expression of a fatty acyl desaturase in the marine teleost Siganus canaliculatus. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1841(7):934–943.  https://doi.org/10.1016/j.bbalip.2014.03.009 Google Scholar
  44. Zhang W, Tsuchiya T, Yasukochi Y (1999) Transitional change in interaction between HIF-1 and HNF-4 in response to hypoxia. J Hum Genet 44(5):293–299.  https://doi.org/10.1007/s100380050163 CrossRefPubMedGoogle Scholar
  45. Zhong W, Mirkovitch J, Darnell J (1994) Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression. Mol Cell Biol 14(11):7276–7284.  https://doi.org/10.1128/MCB.14.11.7276 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Shuqi Wang
    • 1
  • Junliang Chen
    • 1
  • Danli Jiang
    • 1
  • Qinghao Zhang
    • 1
  • Cuihong You
    • 1
  • Douglas R. Tocher
    • 3
  • Óscar Monroig
    • 3
  • Yewei Dong
    • 1
    • 2
  • Yuanyou Li
    • 2
  1. 1.Guangdong Provincial Key Laboratory of Marine BiotechnologyShantou UniversityShantouChina
  2. 2.School of Marine SciencesSouth China Agricultural UniversityGuangzhouChina
  3. 3.Institute of Aquaculture, Faculty of Natural SciencesUniversity of StirlingStirlingUK

Personalised recommendations