Advertisement

Ablation of catalase promotes non-alcoholic fatty liver via oxidative stress and mitochondrial dysfunction in diet-induced obese mice

  • Su-Kyung Shin
  • Hyun-Woo Cho
  • Seung-Eun Song
  • Jae-Hoon Bae
  • Seung-Soon Im
  • Inha Hwang
  • Hunjoo Ha
  • Dae-Kyu SongEmail author
Integrative physiology
  • 80 Downloads
Part of the following topical collections:
  1. Integrative Physiology

Abstract

Hydrogen peroxide (H2O2) produced endogenously can cause mitochondrial dysfunction and metabolic complications in various cell types by inducing oxidative stress. In the liver, oxidative and endoplasmic reticulum (ER) stress affects the development of non-alcoholic fatty liver disease (NAFLD). Although a link between both stresses and fatty liver diseases has been suggested, few studies have investigated the involvement of catalase in fatty liver pathogenesis. We examined whether catalase is associated with NAFLD, using catalase knockout (CKO) mice and the catalase-deficient human hepatoma cell line HepG2. Hepatic morphology analysis revealed that the fat accumulation was more prominent in high-fat diet (HFD) CKO mice compared to that in age-matched wild-type (WT) mice, and lipid peroxidation and H2O2 release were significantly elevated in CKO mice. Transmission electron micrographs indicated that the liver mitochondria from CKO mice tended to be more severely damaged than those in WT mice. Likewise, mitochondrial DNA copy number and cellular ATP concentrations were significantly lower in CKO mice. In fatty acid-treated HepG2 cells, knockdown of catalase accelerated cellular lipid accumulation and depressed mitochondrial biogenesis, which was recovered by co-treatment with N-acetyl cysteine or melatonin. This effect of antioxidant was also true in HFD-fed CKO mice, suppressing fatty liver development and improving hepatic mitochondrial function. Expression of ER stress marker proteins and hepatic fat deposition also increased in normal-diet, aged CKO mice compared to WT mice. These findings suggest that H2O2 production may be an important event triggering NAFLD and that catalase may be an attractive therapeutic target for preventing NAFLD.

Keywords

Catalase Oxidative stress Non-alcoholic fatty liver disease Mitochondrial function Hydrogen peroxide ER stress 

Notes

Author contributions

Shin SK performed most of experiments, analyzed data, and wrote the paper. Cho HW and Song SE performed some experiments. Bae JH and Im SS analyzed data. Ha H and Hwang I reviewed the draft and revised manuscript. Song DK designed study, analyzed data, and wrote the paper.

Funding

This study was supported by a grant from the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (Nos. 2014R1A5A2010008, 2018R1A2B2004429, and 2018R1D1A1B07043068).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (KM2016-08).

Supplementary material

424_2018_2250_MOESM1_ESM.pdf (236 kb)
Online Resource 1 (PDF 235 kb)
424_2018_2250_Fig8_ESM.png (25 kb)
Online Resource 2

Relative mRNA expression of catalase in livers from WT and CKO mice. n = 810, ###P < 0.001 vs. WT-ND. C57BL/6J wild-type, WT; Catalase knockout, CKO; Normal diet, ND; High-fat diet, HFD (PNG 25 kb)

424_2018_2250_MOESM2_ESM.tif (2.4 mb)
High resolution image (TIF 2492 kb)

References

  1. 1.
    Aharoni-Simon M, Hann-Obercyger M, Pen S, Madar Z, Tirosh O (2011) Fatty liver is associated with impaired activity of PPARγ-coactivator 1a (PGC1a) and mitochondrial biogenesis in mice. Lab Investig 91:1018–1028CrossRefGoogle Scholar
  2. 2.
    Bai J, Cederbaum AI (2001) Mitochondrial catalase and oxidative injury. Biol Signals Recept 10:189–199CrossRefGoogle Scholar
  3. 3.
    Bai J, Rodriguez AM, Melendez JA, Cederbaum AI (1999) Overexpression of catalase in cytosolic or mitochondrial compartment protects HepG2 cells against oxidative injury. J Biol Chem 274:26217–26224CrossRefGoogle Scholar
  4. 4.
    Banerjee A, Banerjee V, Czinn S, Blanchard T (2017) Increased reactive oxygen species levels cause ER stress and cytotoxicity in andrographolide treated colon cancer cells. Oncotarget 8(16):26142–26153CrossRefGoogle Scholar
  5. 5.
    Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B (2013) Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 58:1497–1507CrossRefGoogle Scholar
  6. 6.
    Boland ML, Oldham S, Boland BB, Will S, Lapointe JM, Guionaud S, Rhodes CJ, Trevaskis JL (2018) Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction. World J Gastroenterol 24:1748–1765CrossRefGoogle Scholar
  7. 7.
    Bravo R, Gutierrez T, Paredes F, Gatica D, Rodriguez AE, Pedrozo Z, Chiong M, Parra V, Quest AF, Rothermel BA, Lavandero S (2012) Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics. Int J Biochem Cell Biol 44(1):16–20CrossRefGoogle Scholar
  8. 8.
    Caballero F, Fernández A, Matías N, Martínez L, Fucho R, Elena M, Caballeria J, Morales A, Fernández-Checa JC, García-Ruiz C (2010) Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J Biol Chem 285:18528–18536CrossRefGoogle Scholar
  9. 9.
    Cai N, Zhou W, Ye LL, Chen J, Liang QN, Chang G, Chen JJ (2017) The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression. Am J Transl Res 9:3853–3866Google Scholar
  10. 10.
    Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker WD Jr (1999) Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 31:430–434CrossRefGoogle Scholar
  11. 11.
    Carmiel-Haggai M, Cederbaum AI, Nieto N (2005) A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J 19:136–138CrossRefGoogle Scholar
  12. 12.
    Cousin SP, Hügl SR, Wrede CE, Kajio H, Myers MG Jr, Rhodes CJ (2001) Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic β-cell line INS-1. Endocrinology 142:229–240CrossRefGoogle Scholar
  13. 13.
    Dara L, Ji C, Kaplowitz N (2011) The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 53(5):1752–1763CrossRefGoogle Scholar
  14. 14.
    Demeilliers C, Maisonneuve C, Grodet A, Mansouri A, Nguyen R, Tinel M, Lettéron P, Degott C, Feldmann G, Pessayre D, Fromenty B (2002) Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice. Gastroenterology 123:1278–1290CrossRefGoogle Scholar
  15. 15.
    Evans RM, Barish GD, Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355–361CrossRefGoogle Scholar
  16. 16.
    Fu S, Watkins SM, Hotamisligil GS (2012) The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15(5):623–634CrossRefGoogle Scholar
  17. 17.
    Galloway CA, Lee H, Brookes PS, Yoon Y (2014) Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 307:G632–G641CrossRefGoogle Scholar
  18. 18.
    Góth L, Nagy T, Káplár M (2015) Acatalasemia and type 2 diabetes mellitus. Orv Hetil 156:393–398CrossRefGoogle Scholar
  19. 19.
    Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R (2006) Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312:734–737CrossRefGoogle Scholar
  20. 20.
    Heit C, Marshall S, Singh S, Yu X, Charkoftaki G, Zhao H, Orlicky DJ, Fritz KS, Thompson DC, Vasiliou V (2017) Catalase deletion promotes prediabetic phenotype in mice. Free Radical Bio Med 103:48–56CrossRefGoogle Scholar
  21. 21.
    Ho YS, Xiong Y, Ma W, Spector A, Ho DS (2004) Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem 279:32804–32812CrossRefGoogle Scholar
  22. 22.
    Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA (2003) PPARγ coactivator-1α expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations. Am J Physiol Cell Physiol 284:C1669–C1677CrossRefGoogle Scholar
  23. 23.
    Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS (2007) Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol 293:G1–G4CrossRefGoogle Scholar
  24. 24.
    Jornayvaz FR, Shulman GI (2010) Regulation of mitochondrial biogenesis. Essays Biochem 47:69–84CrossRefGoogle Scholar
  25. 25.
    Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, Herder C, Carstensen M, Krausch M, Knoefel WT, Schlensak M, Roden M (2015) Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 21:739–746CrossRefGoogle Scholar
  26. 26.
    Leclercq IA (2004) Antioxidant defence mechanisms: new players in the pathogenesis of non-alcoholic steatohepatitis? Clin Sci (Lond) 106:235–237CrossRefGoogle Scholar
  27. 27.
    Lee AH, Scapa EF, Cohen DE, Glimcher LH (2008) Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320(5882):1492–1496CrossRefGoogle Scholar
  28. 28.
    Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI (2010) Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 12:668–674CrossRefGoogle Scholar
  29. 29.
    Liu Y, Adachi M, Zhao S, Hareyama M, Koong AC, Luo D, Rando TA, Imai K, Shinomura Y (2009) Preventing oxidative stress: a new role for XBP1. Cell Death Differ 16(6):847–857CrossRefGoogle Scholar
  30. 30.
    Liu C, Ma J, Sun J, Cheng C, Feng Z, Jiang H, Yang W (2017) Flavonoid-rich extract of Paulownia fortunei flowers attenuates diet-induced hyperlipidemia, hepatic steatosis and insulin resistance in obesity mice by AMPK pathway. Nutrients 9:E959CrossRefGoogle Scholar
  31. 31.
    Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, Fernández-Checa JC, García-Ruiz C (2011) Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury. J Hepatol 54:1002–1010CrossRefGoogle Scholar
  32. 32.
    Luft JH (1961) Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol 9:409–414CrossRefGoogle Scholar
  33. 33.
    Malhi H, Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54(4):795–809CrossRefGoogle Scholar
  34. 34.
    Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H, Ota T, Yokoyama M, Honda M, Miyamoto K, Kaneko S (2008) Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 57:1071–1077CrossRefGoogle Scholar
  35. 35.
    Moura FA, de Andrade KQ, Araújo ORPD, Nunes-Souza V, Santos JCDF, Rabelo LA, Goulart MOF (2016) Colonic and hepatic modulation by lipoic acid and/or N-acetylcysteine supplementation in mild ulcerative colitis induced by dextran sodium sulfate in rats. Oxidative Med Cell Longev 2016:4047362CrossRefGoogle Scholar
  36. 36.
    Nicholls HT, Kowalski G, Kennedy DJ, Risis S, Zaffino LA, Watson N, Kanellakis P, Watt MJ, Bobik A, Bonen A, Febbraio M, Lancaster GI, Febbraio MA (2011) Hematopoietic cell–restricted deletion of CD36 reduces high-fat diet-induced macrophage infiltration and improves insulin signaling in adipose tissue. Diabetes 60:1100–1110CrossRefGoogle Scholar
  37. 37.
    Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W, Inoue K, Kitazawa R, Kitazawa S, Matsuki Y, Hiramatsu R, , Masubuchi S, Omachi A, Kimura K, Saito M, Amo T, Ohta S, Yamaguchi T, Osumi T, Cheng J, Fujimoto T, Nakao H, Nakao K, Aiba A, Okamura H, Fushiki T, Kasuga M (2008) FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest 118:2808–2821Google Scholar
  38. 38.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461CrossRefGoogle Scholar
  39. 39.
    Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140CrossRefGoogle Scholar
  40. 40.
    Pagliassotti MJ (2012) Endoplasmic reticulum stress in nonalcoholic fatty liver disease. Annu Rev Nutr 32:17–33CrossRefGoogle Scholar
  41. 41.
    Park JH, Shim HM, Na AY, Bae KC, Bae JH, Im SS, Cho HC, Song DK (2014) Melatonin prevents pancreaticβ-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress. J Pineal Res 56:143–153CrossRefGoogle Scholar
  42. 42.
    Patterson RE, Kalavalapalli S, Williams CM, Nautiyal M, Mathew JT, Martinez J, Reinhard MK, McDougall DJ, Rocca JR, Yost RA, Cusi K, Garrett TJ, Sunny NE (2016) Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity. Am J Physiol Endocrinol Metab 310:E484–E494CrossRefGoogle Scholar
  43. 43.
    Pérez-Carreras M, Del Hoyo P, Martín MA, Rubio JC, Martín A, Castellano G, Colina F, Arenas J, Solis-Herruzo JA (2003) Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38:999–1007CrossRefGoogle Scholar
  44. 44.
    Pessayre D, Fromenty B (2005) NASH: a mitochondrial disease. J Hepatol 42:928–940CrossRefGoogle Scholar
  45. 45.
    Piao L, Choi J, Kwon G, Ha H (2017) Endogenous catalase delays high-fat diet-induced liver injury in mice. Korean J Physiol Phamacol 21:317–325CrossRefGoogle Scholar
  46. 46.
    Reid BN, Ables GP, Otlivanchik OA, Schoiswohl G, Zechner R, Blaner WS, Goldberg IJ, Schwabe RF, Chua SC Jr, Huang LS (2008) Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J Biol Chem 283:13087–13099CrossRefGoogle Scholar
  47. 47.
    Reynolds ES (1963) The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J Cell Biol 17:208–212CrossRefGoogle Scholar
  48. 48.
    Rolo AP, Teodoro JS, Palmeira CM (2012) Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Bio Med 52:59–69CrossRefGoogle Scholar
  49. 49.
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192CrossRefGoogle Scholar
  50. 50.
    Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L, Sunny NE, He T, Nair LA, Livingston KA, Fu X, Merritt ME, Sherry AD, Malloy CR, Shelton JM, Lambert J, Parks EJ, Corbin I, Magnuson MA, Browning JD, Burgess SC (2015) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 125:4447–4462CrossRefGoogle Scholar
  51. 51.
    Serra D, Mera P, Malandrino MI, Mir JF, Herrero L (2013) Mitochondrial fatty acid oxidation in obesity. Antioxid Redox Signal 19:269–284CrossRefGoogle Scholar
  52. 52.
    Shin SK, Cho HW, Song SE, Song DK (2018) Catalase and nonalcoholic fatty liver disease. Pflugers Arch 470(12):1721–1737CrossRefGoogle Scholar
  53. 53.
    Shokolenko I, Venediktova N, Bochkareva A, Wilson GL, Alexeyev MF (2009) Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res 37:2539–2548CrossRefGoogle Scholar
  54. 54.
    Steinbrenner H, Sies H (2009) Protection against reactive oxygen species by selenoproteins. Biochim Biophys Acta 1790:1478–1485CrossRefGoogle Scholar
  55. 55.
    Tontonoz P, Spiegelman BM (2008) Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem 77:289–312CrossRefGoogle Scholar
  56. 56.
    Vacca M, Degirolamo C, Mariani-Costantini R, Palasciano G, Moschetta A (2011) Lipid-sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome. Wiley Interdiscip Rev Syst Biol Med 3:562–587Google Scholar
  57. 57.
    Valdecantos MP, Pérez-Matute P, González-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martínez JA (2012) Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3. Obesity 20:1974–1983CrossRefGoogle Scholar
  58. 58.
    Vial G, Dubouchaud H, Couturier K, Cottet-Rousselle C, Taleux N, Athias A, Galinier A, Casteilla L, Leverve XM (2011) Effects of a high-fat diet on energy metabolism and ROS production in rat liver. J Hepatol 54:348–356CrossRefGoogle Scholar
  59. 59.
    Virbasius JV, Scarpulla RC (1994) Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A 91:1309–1313CrossRefGoogle Scholar
  60. 60.
    Wang S, Moustaid-Moussa N, Chen L, Mo H, Shastri A, Su R, Bapat P, Kwun I, Shen CL (2014) Novel insights of dietary polyphenols and obesity. J Nutr Biochem 25:1–18CrossRefGoogle Scholar
  61. 61.
    Watson ML (1958) Staining of tissue sections for electron microscopy with heavy metals. J Biophys Biochem Cytol 4:475–478CrossRefGoogle Scholar
  62. 62.
    Way JM, Harrington WW, Brown KK, Gottschalk WK, Sundseth SS, Mansfield TA, Ramachandran RK, Willson TM, Kliewer SA (2001) Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor γ activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. Endocrinology 142:1269–1277CrossRefGoogle Scholar
  63. 63.
    Yki-Järvinen H (2015) Nutritional modulation of non-alcoholic fatty liver disease and insulin resistance. Nutrients 7:9127–9138CrossRefGoogle Scholar
  64. 64.
    Yu T, Robotham JL, Yoon Y (2006) Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A 103:2653–2658CrossRefGoogle Scholar
  65. 65.
    Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R (2005) Lipolysis: pathway under construction. Curr Opin Lipidol 16:333–340CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Physiology & Obesity-mediated Disease Research CenterKeimyung University School of MedicineDaeguSouth Korea
  2. 2.Graduate School of Pharmaceutical Sciences, College of PharmacyEwha Women’s UniversitySeoulSouth Korea

Personalised recommendations