Skip to main content
SpringerLink
Log in

Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The temporal relationship of hepatic steatosis and changes in liver oxidative stress and fatty acid (FA) composition to the development of non-alcoholic steatohepatitis (NASH) remain to be clearly defined. Recently, we developed an experimental model of hepatic steatosis and NASH, the transgenic spontaneously hypertensive rat (SHR) that overexpresses a dominant positive form of the human SREBP-1a isoform in the liver. These rats are genetically predisposed to hepatic steatosis at a young age that ultimately progresses to NASH in older animals. Young transgenic SHR versus SHR controls exhibited simple hepatic steatosis which was associated with significantly increased hepatic levels of oxidative stress markers, conjugated dienes, and TBARS, with decreased levels of antioxidative enzymes and glutathione and lower concentrations of plasma α- and γ-tocopherol. Transgenic rats exhibited increased plasma levels of saturated FA, decreased levels of n−3 and n−6 polyunsaturated FA (PUFA), and increased n−6/n−3 PUFA ratios. These results are consistent with the hypothesis that excess fat accumulation in the liver in association with increased oxidative stress and disturbances in the metabolism of saturated and unsaturated fatty acids may precede and contribute to the primary pathogenesis of NASH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Clark JM (2006) The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40(3 Suppl 1):S5–S10

    PubMed  Google Scholar 

  2. Rector RS, Thyfault JP, Wei Y, Ibdah JA (2008) Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World J Gastroenterol 14:185–192

    Article  CAS  PubMed  Google Scholar 

  3. Schreuder TC, Verwer BJ, van Nieuwkerk CM, Mulder CJ (2008) Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol 14:2474–2486

    Article  CAS  PubMed  Google Scholar 

  4. Day CP, James OFW (1998) Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology 114:842–845

    Article  CAS  PubMed  Google Scholar 

  5. Gawrieh S, Opara EC, Koch TR (2004) Oxidative stress in nonalcoholic fatty liver disease: pathogenesis and antioxidant therapies. J Investig Med 52:506–514

    CAS  PubMed  Google Scholar 

  6. Videla LA, Rodrigo R, Araya J, Poniachik J (2006) Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trend Mol Med 12:555–558

    Article  CAS  Google Scholar 

  7. Wanless IR, Lentz JS (1990) Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12:1106–1110

    Article  CAS  PubMed  Google Scholar 

  8. Allard JP, Aghdassi E, Mohammed S, Raman M, Avand G, Arendt BM, Jalali P, Kandasamy T, Prayitno N, Sherman M, Guindi M, Ma DW, Heathcote JE (2008) Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study. J Hepatol 48:300–307

    Article  CAS  PubMed  Google Scholar 

  9. Araya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, Poniachik J (2004) Increase in long-chain polyunsaturated fatty acid n−6/n−3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 106:635–643

    Article  CAS  Google Scholar 

  10. Gentile CL, Pagliassotti MJ (2008) The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem 19:567–576

    Article  CAS  PubMed  Google Scholar 

  11. Qi NR, Wang J, Zidek V, Landa V, Mlejnek P, Kazdová L, Pravenec M, Kurtz TW (2005) A new transgenic rat model of hepatic steatosis and the metabolic syndrome. Hypertension 45:1004–1011

    Article  CAS  PubMed  Google Scholar 

  12. Concetti A, Massei P, Rotilio G, Brunori M, Rachmilewitz EA (1976) Superoxide dismutase in red blood cells: method of assay and enzyme content in normal subjects and in patients with beta-thalassemia (major and intermedia). J Lab Clin Med 87:1057–1064

    CAS  PubMed  Google Scholar 

  13. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  14. Kagawa Y, Uchida E, Yokota H, Yamaguchi M, Taniyama H (1998) Immunohistochemical localization of apolipoprotein B-100 (ApoB-100) and expression of glutathione peroxidase (GSH-PO) in canine atherosclerotic lesions. Vet Pathol 35:227–229

    CAS  PubMed  Google Scholar 

  15. Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and non-protein sulfhydryl groups in tissue with Elman’s reagent. Anal Biochem 25:192–205

    Article  CAS  PubMed  Google Scholar 

  16. Ward PJ, Pill GO, Hatherill JR (1985) Systemic complement activation, lung injury and products of lipid peroxidation. J Clin Invest 76:517–527

    Article  CAS  PubMed  Google Scholar 

  17. Yokode M, Kita T, Kikawa Y, Ogorochi T, Narumiya S, Kawai C (1988) Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein. J Clin Invest 81:720–729

    Article  CAS  PubMed  Google Scholar 

  18. Catignani GL (1986) An HPLC method for the simultaneous determination of retinol and alpha-tocopherol in plasma or serum. Methods Enzymol 123:215–219

    Article  CAS  PubMed  Google Scholar 

  19. Kiyose C, Saito H, Ueda H, Igarashi O (2001) Simultaneous determination of alpha- and gamma-tocopherol and their quinones in rats plasma and tissues using reversed-phase high performance liquid chromatography. J Nutr Sci Vitaminol 47:102–107

    CAS  PubMed  Google Scholar 

  20. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509

    CAS  PubMed  Google Scholar 

  21. Bahcecioglu IH, Yalniz M, IIhau N, Ataseven H, Ozercan IH (2005) Levels of serum vitamin A, alpha-tocopherol and malondialdehyde in patients with non-alcoholic steatohepatitis: relationship with histopathologic severity. Int J Clin Pract 59:318–323

    Article  CAS  PubMed  Google Scholar 

  22. Alwayn IP, Gura K, Nose V, Zausche B, Javid P, Garza J, Verbesey J, Voss S, Ollero M, Andersson C, Bistrian B, Folkman J, Puder M (2005) Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res 57:445–452

    Article  CAS  PubMed  Google Scholar 

  23. Calder PC (2007) Immunomodulation by omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 77:327–335

    Article  CAS  PubMed  Google Scholar 

  24. Nakamura MT, Cho HP, Clarke SD (2000) Regulation of hepatic Δ-6 desaturase expression and its role in the polyunsaturated fatty acid inhibition of fatty acid synthase gene expression in mice. J Nutr 130:1561–1565

    CAS  PubMed  Google Scholar 

  25. Ghafoorunissa G, Ibrahim A, Rajkumar L, Acharya V (2005) Dietary (n−3) long chain polyunsaturated fatty acids prevent sucrose-induced insulin resistance in rats. J Nutr 135:2634–2638

    CAS  PubMed  Google Scholar 

  26. Griffin MD, Sanders TA, Davies IG, Morgan LM, Millward DJ, Lewis F, Slaughter S, Cooper JA, Miller GJ, Griffin BA (2006) Effects of altering the ratio of dietary n−6 to n−3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45–70 y: the OPTILIP Study. Am J Clin Nutr 84:1290–1298

    CAS  PubMed  Google Scholar 

  27. Sjögren P, Sierra-Johnson J, Gertow K, Rosell M, Vessby B, de Faire U, Hamsten A, Hellenius ML, Fisher RM (2008) Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance. Diabetologia 51:328–335

    Article  PubMed  CAS  Google Scholar 

  28. Comte C, Bellenger S, Bellenger J, Tessier C, Poisson JP, Narce M (2004) Effects of streptozotocin and dietary fructose on delta-6 desaturation in spontaneously hypertensive rat liver. Biochimie 86:799–806

    Article  CAS  PubMed  Google Scholar 

  29. Brenner RR, Rimoldi OJ, Lombardo YB, González MS, Bernasconi AM, Chicco A, Basabe JC (2003) Desaturase activities in rat model of insulin resistance induced by a sucrose-rich diet. Lipids 38:733–742

    Article  CAS  PubMed  Google Scholar 

  30. Gasperikova D, Demcakova E, Ukropec J, Klimes I, Sebokova E (2002) Insulin resistance in the hereditary hypertriglyceridemic rat is associated with an impairment of delta-6 desaturase expression in liver. Ann N Y Acad Sci 967:446–453

    CAS  PubMed  Google Scholar 

  31. Vessby B, Gustafsson IB, Tengblad S, Boberg M, Andersson A (2002) Desaturation and elongation of fatty acids and insulin action. Ann N Y Acad Sci 967:183–195

    Article  CAS  PubMed  Google Scholar 

  32. Perlemuter G, Davit-Spraul A, Cosson C, Conti M, Bigorgne A, Paradis V, Corre MP, Prat L, Kuoch V, Basdevant A, Pelletier G, Oppert JM, Buffet C (2005) Increase in liver antioxidant enzyme activities in non-alcoholic fatty liver disease. Liver Int 25:946–953

    Article  CAS  PubMed  Google Scholar 

  33. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quiñones L, Varela N, Contreras J, Lazarte R, Csendes A, Rojas J, Maluenda F, Burdiles P, Diaz JC, Smok G, Thielemann L, Poniachik J (2004) Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci (Lond) 106:261–268

    Article  CAS  Google Scholar 

  34. Koruk M, Taysi S, Savas MC (2004) Oxidative stress and enzymatic antioxidant status in patients with nonalcoholic steatohepatitis. Ann Clin Lab Sci 34:57–62

    CAS  PubMed  Google Scholar 

  35. Nobili V, Pastore A, Gaeta LM, Tozzi G, Comparcola D, Sartorelli MR, Marcellini M, Bertini E, Piemonte F (2005) Glutathione metabolism and antioxidant enzymes in patients affected by nonalcoholic steatohepatitis. Clin Chim Acta 355:105–111

    Article  CAS  PubMed  Google Scholar 

  36. Elizondo A, Araya J, Rodrigo R, Poniachik J, Csendes A, Maluenda F, Díaz JC, Signorini C, Sgherri C, Comporti M, Videla LA (2007) Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients. Obesity (Silver Spring) 15:24–31

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institutes of Health grants HL35018, HL56028, and HL63709 (T.W.K) and by grant IAA500110604 from the Czech Academy of Sciences, grants NR9387 and NR9359 from the Ministry of Health of the Czech Republic and the European Commission within the Sixth Framework Programme through the Integrated Project EURATools (contract no. LSHG-CT-2005-019015) (M.P.). M.P. is an international research scholar of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Institute for Clinical and Experimental Medicine, Prague, Czech Republic

    Hana Malínská, Olena Oliyarnyk, Miriam Hubová & Ludmila Kazdová

  2. Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220, Prague 4, Czech Republic

    Václav Zídek, Vladimír Landa, Miroslava Šimáková, Petr Mlejnek & Michal Pravenec

  3. University of California, San Francisco, USA

    Theodore W. Kurtz

Authors
  1. Hana Malínská
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olena Oliyarnyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miriam Hubová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Václav Zídek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vladimír Landa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miroslava Šimáková
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Petr Mlejnek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ludmila Kazdová
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Theodore W. Kurtz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michal Pravenec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michal Pravenec.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Malínská, H., Oliyarnyk, O., Hubová, M. et al. Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis. Mol Cell Biochem 335, 119–125 (2010). https://doi.org/10.1007/s11010-009-0248-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-009-0248-5

Keywords

Search

Navigation