Nutrition Research and Practice

The Korean Nutrition Society (한국영양학회)
권호 표지
DOI QR코드

DOI QR Code

Free fatty acid-induced histone acetyltransferase activity accelerates lipid accumulation in HepG2 cells

  • Received : 2018.09.13
  • Accepted : 2019.02.12
  • Published : 2019.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

BACKGROUND/OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease triggered by epigenetic alterations, including lysine acetylation at histone or non-histone proteins, affecting the stability or transcription of lipogenic genes. Although various natural dietary compounds have anti-lipogenic effects, their effects on the acetylation status and lipid metabolism in the liver have not been thoroughly investigated. MATERIALS/METHODS: Following oleic-palmitic acid (OPA)-induced lipid accumulation in HepG2 cells, the acetylation status of histone and non-histone proteins, HAT activity, and mRNA expression of representative lipogenic genes, including $PPAR{\gamma}$, SREBP-1c, ACLY, and FASN, were evaluated. Furthermore, correlations between lipid accumulation and HAT activity for 22 representative natural food extracts (NExs) were evaluated. RESULTS: Non-histone protein acetylation increased following OPA treatment and the acetylation of histones H3K9, H4K8, and H4K16 was accelerated, accompanied by an increase in HAT activity. OPA-induced increases in the mRNA expression of lipogenic genes were down-regulated by C-646, a p300/CBP-specific inhibitor. Finally, we detected a positive correlation between HAT activity and lipid accumulation (Pearson's correlation coefficient = 0.604) using 22 NExs. CONCLUSIONS: Our results suggest that NExs have novel applications as nutraceutical agents with HAT inhibitor activity for the prevention and treatment of NAFLD.

Keywords

References

  1. Ahmed MH, Husain NE, Almobarak AO. Nonalcoholic Fatty liver disease and risk of diabetes and cardiovascular disease: what is important for primary care physicians? J Family Med Prim Care 2015;4:45-52. https://doi.org/10.4103/2249-4863.152252
  2. Sun C, Fan JG, Qiao L. Potential epigenetic mechanism in non-alcoholic fatty liver disease. Int J Mol Sci 2015;16:5161-79. https://doi.org/10.3390/ijms16035161
  3. Wang Q, Guo S, Gao Y. Protein lysine acetylated/deacetylated enzymes and the metabolism-related diseases. Adv Biosci Biotechnol 2016;7:454-67. https://doi.org/10.4236/abb.2016.711044
  4. Castano-Cerezo S, Bernal V, Post H, Fuhrer T, Cappadona S, Sanchez-Diaz NC, Sauer U, Heck AJ, Altelaar AF, Canovas M. Protein acetylation affects acetate metabolism, motility and acid stress response in Escherichia coli. Mol Syst Biol 2014;10:762. https://doi.org/10.15252/msb.20145227
  5. van Noort V, Seebacher J, Bader S, Mohammed S, Vonkova I, Betts MJ, Kuhner S, Kumar R, Maier T, O'Flaherty M, Rybin V, Schmeisky A, Yus E, Stulke J, Serrano L, Russell RB, Heck AJ, Bork P, Gavin AC. Cross-talk between phosphorylation and lysine acetylation in a genome-reduced bacterium. Mol Syst Biol 2012;8:571. https://doi.org/10.1038/msb.2012.4
  6. Yu BJ, Kim JA, Moon JH, Ryu SE, Pan JG. The diversity of lysine-acetylated proteins in Escherichia coli. J Microbiol Biotechnol 2008;18:1529-36.
  7. Kim D, Yu BJ, Kim JA, Lee YJ, Choi SG, Kang S, Pan JG. The acetylproteome of Gram-positive model bacterium Bacillus subtilis. Proteomics 2013;13:1726-36. https://doi.org/10.1002/pmic.201200001
  8. Fukushima A, Lopaschuk GD. Acetylation control of cardiac fatty acid ${\beta}$-oxidation and energy metabolism in obesity, diabetes, and heart failure. Biochim Biophys Acta 2016;1862:2211-20. https://doi.org/10.1016/j.bbadis.2016.07.020
  9. LaBarge S, Migdal C, Schenk S. Is acetylation a metabolic rheostat that regulates skeletal muscle insulin action? Mol Cells 2015;38:297-303. https://doi.org/10.14348/molcells.2015.0020
  10. Clayton AL, Hazzalin CA, Mahadevan LC. Enhanced histone acetylation and transcription: a dynamic perspective. Mol Cell 2006;23:289-96. https://doi.org/10.1016/j.molcel.2006.06.017
  11. Yang XJ, Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 2008;9:206-18. https://doi.org/10.1038/nrm2346
  12. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009;10:32-42. https://doi.org/10.1038/nrg2485
  13. Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL. Regulation of cellular metabolism by protein lysine acetylation. Science 2010;327:1000-4. https://doi.org/10.1126/science.1179689
  14. Wang Q, Zhang Y, Yang C, Xiong H, Lin Y, Yao J, Li H, Xie L, Zhao W, Yao Y, Ning ZB, Zeng R, Xiong Y, Guan KL, Zhao S, Zhao GP. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 2010;327:1004-7. https://doi.org/10.1126/science.1179687
  15. Podrini C, Borghesan M, Greco A, Pazienza V, Mazzoccoli G, Vinciguerra M. Redox homeostasis and epigenetics in non-alcoholic fatty liver disease (NAFLD). Curr Pharm Des 2013;19:2737-46. https://doi.org/10.2174/1381612811319150009
  16. Xu X, So JS, Park JG, Lee AH. Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin Liver Dis 2013;33:301-11. https://doi.org/10.1055/s-0033-1358523
  17. Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest 2010;120:4316-31. https://doi.org/10.1172/JCI41624
  18. Shankar E, Kanwal R, Candamo M, Gupta S. Dietary phytochemicals as epigenetic modifiers in cancer: promise and challenges. Semin Cancer Biol 2016;40-41:82-99. https://doi.org/10.1016/j.semcancer.2016.04.002
  19. Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, Cui J, Taylor KD, Wilson L, Cummings OW, Chen YD, Rotter JI; Nonalcoholic Steatohepatitis Clinical Research Network. Genomewide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 2010;139:1567-76, 1576.e1-6. https://doi.org/10.1053/j.gastro.2010.07.057
  20. Hwang JT, Shin EJ, Chung MY, Park JH, Chung S, Choi HK. Ethanol extract of Allium fistulosum inhibits development of non-alcoholic fatty liver disease. Nutr Res Pract 2018;12:110-7. https://doi.org/10.4162/nrp.2018.12.2.110
  21. Choi KC, Jung MG, Lee YH, Yoon JC, Kwon SH, Kang HB, Kim MJ, Cha JH, Kim YJ, Jun WJ, Lee JM, Yoon HG. Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer Res 2009;69:583-92. https://doi.org/10.1158/0008-5472.CAN-08-2442
  22. Pan MH, Lai CS, Tsai ML, Ho CT. Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds. Mol Nutr Food Res 2014;58:147-71. https://doi.org/10.1002/mnfr.201300522
  23. Pirola CJ, Gianotti TF, Burgueno AL, Rey-Funes M, Loidl CF, Mallardi P, Martino JS, Castano GO, Sookoian S. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 2013;62:1356-63. https://doi.org/10.1136/gutjnl-2012-302962
  24. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013;10:645-55. https://doi.org/10.1038/nrgastro.2013.182
  25. Afonso MB, Rodrigues PM, Simao AL, Castro RE. Circulating microRNAs as potential biomarkers in non-alcoholic fatty liver disease and hepatocellular carcinoma. J Clin Med 2016;5:30. https://doi.org/10.3390/jcm5030030
  26. Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, Epstein JA, Gruber PJ. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J 2008;22:3549-60. https://doi.org/10.1096/fj.08-108548
  27. Tian Y, Wong VW, Chan HL, Cheng AS. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin Cancer Biol 2013;23:471-82. https://doi.org/10.1016/j.semcancer.2013.08.010
  28. Lo KA, Bauchmann MK, Baumann AP, Donahue CJ, Thiede MA, Hayes LS, des Etages SA, Fraenkel E. Genome-wide profiling of H3K56 acetylation and transcription factor binding sites in human adipocytes. PLoS One 2011;6:e19778. https://doi.org/10.1371/journal.pone.0019778
  29. Mikula M, Majewska A, Ledwon JK, Dzwonek A, Ostrowski J. Obesity increases histone H3 lysine 9 and 18 acetylation at Tnfa and Ccl2 genes in mouse liver. Int J Mol Med 2014;34:1647-54. https://doi.org/10.3892/ijmm.2014.1958
  30. Alrob OA, Sankaralingam S, Ma C, Wagg CS, Fillmore N, Jaswal JS, Sack MN, Lehner R, Gupta MP, Michelakis ED, Padwal RS, Johnstone DE, Sharma AM, Lopaschuk GD. Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc Res 2014;103:485-97. https://doi.org/10.1093/cvr/cvu156
  31. Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010;285:33959-70. https://doi.org/10.1074/jbc.M110.122978
  32. Sterner DE, Berger SL. Acetylation of histones and transcriptionrelated factors. Microbiol Mol Biol Rev 2000;64:435-59. https://doi.org/10.1128/MMBR.64.2.435-459.2000
  33. Verdone L, Agricola E, Caserta M, Di Mauro E. Histone acetylation in gene regulation. Brief Funct Genomics Proteomics 2006;5:209-21. https://doi.org/10.1093/bfgp/ell028
  34. Kurdistani SK, Grunstein M. Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol 2003;4:276-84. https://doi.org/10.1038/nrm1075
  35. Fajas L, Schoonjans K, Gelman L, Kim JB, Najib J, Martin G, Fruchart JC, Briggs M, Spiegelman BM, Auwerx J. Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism. Mol Cell Biol 1999;19:5495-503. https://doi.org/10.1128/MCB.19.8.5495
  36. Pettinelli P, Videla LA. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab 2011;96:1424-30. https://doi.org/10.1210/jc.2010-2129
  37. Tolman KG, Dalpiaz AS. Treatment of non-alcoholic fatty liver disease. Ther Clin Risk Manag 2007;3:1153-63.
  38. Rodgers RJ, Tschop MH, Wilding JP. Anti-obesity drugs: past, present and future. Dis Model Mech 2012;5:621-6. https://doi.org/10.1242/dmm.009621
  39. Ann JY, Eo H, Lim Y. Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice. Genes Nutr 2015;10:46. https://doi.org/10.1007/s12263-015-0495-x
  40. Sun JH, Liu X, Cong LX, Li H, Zhang CY, Chen JG, Wang CM. Metabolomics study of the therapeutic mechanism of Schisandra Chinensis lignans in diet-induced hyperlipidemia mice. Lipids Health Dis 2017;16:145. https://doi.org/10.1186/s12944-017-0533-3

Cited by

  1. Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease vol.12, 2019, https://doi.org/10.3389/fphar.2021.784591
  2. 3,4-dihydroxytoluene, a metabolite of rutin, suppresses the progression of nonalcoholic fatty liver disease in mice by inhibiting p300 histone acetyltransferase activity vol.42, pp.9, 2021, https://doi.org/10.1038/s41401-020-00571-7
  3. Proteome analysis identified proteins associated with mitochondrial function and inflammation activation crucially regulating the pathogenesis of fatty liver disease vol.22, pp.1, 2019, https://doi.org/10.1186/s12864-021-07950-2