Comparative Clinical Pathology

, Volume 28, Issue 1, pp 203–209 | Cite as

PPAR-α agonist fenofibrate potentiates antioxidative elements and improves oxidative stress of hepatic cells in streptozotocin-induced diabetic animals

  • Habib YaribeygiEmail author
  • Mohammad Taghi Mohammadi
  • Alexandra E. Butler
  • Amirhossein SahebkarEmail author
Original Article


Oxidative stress induced by hyperglycemia has a crucial role in hepatocellular disorders. The aim of this study was to evaluate whether fenofibrate potentiates the anti-oxidant defense system of hepatocytes and thereby prevents oxidative stress. Male Wistar rats were assigned to four groups: normal control (C), normal-treated (CF), diabetic (D), and diabetic-treated (DF) (n = 6 per group). Hyperglycemia was induced with streptozotocin (single dose of 45 mg/kg into the tail vein). Treated groups received fenofibrate for 8 weeks by intragastric gavage (80 mg/kg/day). At study completion (day 56), the rats were sacrificed and liver tissue harvested. Catalase (CAT) and superoxide dismutase (SOD) enzymes activities, malondialdehyde (MDA), nitrate, and glutathione (GLT) contents were evaluated in all experimental groups. Obtained data were analyzed via two-way ANOVA, p < 0.05 taken as significant. Hyperglycemia markedly decreased SOD and CAT enzyme activities; furthermore, oxidative stress was induced via MDA content enhancement. Fenofibrate increased both SOD and CAT enzyme activities and decreased the nitrate content and MDA production in hepatic cells, thus improving oxidative stress. Our data suggest that uncontrolled hyperglycemia overwhelms the anti-oxidant defense systems of hepatic cells and oxidative damage ensues. The PPAR-α agonist Fenofibrate prevents oxidative damage in hepatocytes by potentiating the anti-oxidant defense system and can therefore improve the redox state in hepatocellular tissue.


Oxidative stress Liver PPAR-α Fenofibrate Malondialdehyde 



This study was carried out by a grant from the School of Medicine of the Baqiyatallah University of Medical Sciences. We wish to thank the Department of Physiology and Biophysics and the Deputy of Research of the Medical School of Baqiyatallah University and also the Clinical Research Development Center of the Baqiyatallah Hospital for providing technical support.


This study was financially supported by the Baqiyatallah University of Medical Sciences, Tehran, Iran.

Compliance with ethical standards

This manuscript complies with the ethical standards of Comparative Clinical Pathology.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval and informed consent

All protocols of the study were approved by the Ethics Committee of the Baqiyatallah University of Medical Sciences. Informed consent was not applicable for this animal study.


  1. Aebi H (1984) [13] Catalase in vitro. In: Methods enzymol, vol 105. Elsevier, pp 121–126Google Scholar
  2. Asmat U, Abad K, Ismail K (2016) Diabetes mellitus and oxidative stress—a concise review. Saudi Pharm J 24:547–553CrossRefGoogle Scholar
  3. Chung HW et al (2011) High-fat diet-induced renal cell apoptosis and oxidative stress in spontaneously hypertensive rat are ameliorated by fenofibrate through the PPARα–FoxO3a–PGC-1α pathway. Nephrol Dial Transplant 27:2213–2225CrossRefGoogle Scholar
  4. Cichoż-Lach H, Michalak A (2014) Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 20:8082CrossRefGoogle Scholar
  5. Derosa G, Maffioli P, Sahebkar A (2015) Plasma uric acid concentrations are reduced by fenofibrate: a systematic review and meta-analysis of randomized placebo-controlled trials. Pharmacol Res 102:63–70. CrossRefGoogle Scholar
  6. Derosa G, Sahebkar A, Maffioli P (2018) The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol 233:153–161. CrossRefGoogle Scholar
  7. Gentric G, Maillet V, Paradis V, Couton D, L’Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S, Desdouets C (2015) Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 125:981–992CrossRefGoogle Scholar
  8. Granger DL, Taintor RR, Boockvar KS, Hibbs Jr JB (1996) Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. In: Methods Enzymol, vol 268. Elsevier, pp 142–151Google Scholar
  9. Gureev A, Shmatkova M, Bashmakov VY, Starkov A, Popov V (2016) The effect of fenofibrate on expression of genes involved in fatty acids beta-oxidation and associated free-radical processes. Biochem Mosc Suppl Ser B Biomed Chem 10:70–74CrossRefGoogle Scholar
  10. Halliwell B, Gutteridge JM (2015) Free radicals in biology and medicine. Oxford University Press, OxfordCrossRefGoogle Scholar
  11. Hou X, Shen YH, Li C, Wang F, Zhang C, Bu P, Zhang Y (2010) PPARα agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity. Biochem Biophys Res Commun 394:653–659CrossRefGoogle Scholar
  12. Ibarra-Lara L, Hong E, Soria-Castro E, Torres-Narváez JC, Pérez-Severiano F, del Valle-Mondragón L, Cervantes-Pérez LG, Ramírez-Ortega M, Pastelín-Hernández GS, Sánchez-Mendoza A (2012) Clofibrate PPARα activation reduces oxidative stress and improves ultrastructure and ventricular hemodynamics in no-flow myocardial ischemia. J Cardiovasc Pharmacol 60:323–334CrossRefGoogle Scholar
  13. Kakkar R, Mantha SV, Radhi J, Prasad K, Kalra J (1998) Increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes. Clin Sci 94:623–632CrossRefGoogle Scholar
  14. Kawada T, Goto T, Takahashi H, Chi H-Y, Ichip N, Nakata K (2018) PPAR-alpha activator, pharmaceutical composition, food and drink, food additive, supplement and method of manufacturing the same. Google PatentsGoogle Scholar
  15. Li S, Tan H-Y, Wang N, Zhang Z-J, Lao L, Wong C-W, Feng Y (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16:26087–26124CrossRefGoogle Scholar
  16. Reyes-Gordillo K, Shah R, Muriel P (2017) Oxidative stress and inflammation in hepatic diseases: current and future therapy. Oxidative Med Cell Longev 2017Google Scholar
  17. Rochette L, Zeller M, Cottin Y, Vergely C (2014) Diabetes, oxidative stress and therapeutic strategies. Biochim Biophys Acta Gen Subj 1840:2709–2729CrossRefGoogle Scholar
  18. Sahebkar A, Watts GF (2013) Fibrate therapy and circulating adiponectin concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials. Atherosclerosis 230:110–120. CrossRefGoogle Scholar
  19. Sahebkar A, Watts GF (2014) Role of selective peroxisome proliferator-activated receptor modulators in managing cardiometabolic disease: tale of a roller-coaster. Diabetes Obes Metab 16:780–792. CrossRefGoogle Scholar
  20. Sahebkar A, Chew GT, Watts GF (2014a) New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin Pharmacother 15:493–503. CrossRefGoogle Scholar
  21. Sahebkar A, Chew GT, Watts GF (2014b) Recent advances in pharmacotherapy for hypertriglyceridemia. Prog Lipid Res 56:47–66. CrossRefGoogle Scholar
  22. Sahebkar A, Giua R, Pedone C, Ray KK, Vallejo-Vaz AJ, Costanzo L (2016a) Fibrate therapy and flow-mediated dilation: a systematic review and meta-analysis of randomized placebo-controlled trials. Pharmacol Res 111:163–179. CrossRefGoogle Scholar
  23. Sahebkar A, Hernández-Aguilera A, Abelló D, Sancho E, Camps J, Joven J (2016b) Systematic review and meta-analysis deciphering the impact of fibrates on paraoxonase-1 status. Metab Clin Exp 65:609–622. CrossRefGoogle Scholar
  24. Sahebkar A, Serban MC, Mikhailidis DP, Toth PP, Muntner P, Ursoniu S, Mosterou S, Glasser S, Martin SS, Jones SR, Rizzo M, Rysz J, Sniderman AD, Pencina MJ, Banach M, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group (2016c) Head-to-head comparison of statins versus fibrates in reducing plasma fibrinogen concentrations: a systematic review and meta-analysis. Pharmacol Res 103:236–252. CrossRefGoogle Scholar
  25. Sahebkar A, Simental-Mendía LE, Watts GF, Serban MC, Banach M (2017) Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials. BMC Med 15:22. CrossRefGoogle Scholar
  26. Sakaguchi S, Takahashi S, Sasaki T, Kumagai T, Nagata K (2011) Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress. Drug Metab Pharmacokinet 26:30–46CrossRefGoogle Scholar
  27. Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N, Sasaki T, Tsujioka K, Makino H, Kashihara N (2005) NAD (P) H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Ren Physiol 288:F1144–F1152CrossRefGoogle Scholar
  28. Simental-Mendía LE, Simental-Mendía M, Sánchez-García A, Banach M, Atkin SL, Gotto AM, Sahebkar A (2018) Effect of fibrates on glycemic parameters: a systematic review and meta-analysis of randomized placebo-controlled trials Pharmacol Res doi:
  29. Sindhu RK, Koo JR, Roberts CK, Vaziri ND (2004) Dysregulation of hepatic superoxide dismutase, catalase and glutathione peroxidase in diabetes: response to insulin and antioxidant therapies. Clin Exp Hypertens 26:43–53CrossRefGoogle Scholar
  30. Tangvarasittichai S (2015) Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 6:456–480CrossRefGoogle Scholar
  31. Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27:502–522CrossRefGoogle Scholar
  32. Walker AE, Kaplon RE, Lucking SMS, Russell-Nowlan MJ, Eckel RH, Seals DR (2012) Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults novelty and significance. Hypertension 60:1517–1523CrossRefGoogle Scholar
  33. Wang G, Liu X, Guo Q, Namura S (2010) Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels. Brain Res 1359:247–255CrossRefGoogle Scholar
  34. Winterbourn CC, Hawkins RE, Brian M, Carrell R (1975) The estimation of red cell superoxide dismutase activity. J Lab Clin Med 85:337–341Google Scholar
  35. Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, Lau TYH, Fung ML, Tipoe GL (2014) Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr 53:187–199CrossRefGoogle Scholar
  36. Yaribeygi H, Farrokhi FR, Rezaee R, Sahebkar A (2017) Oxidative stress induces renal failure: A review of possible molecular pathways. J Cell Biochem 119:2990–2998CrossRefGoogle Scholar
  37. Yaribeygi H, Faghihi N, Mohammadi MT, Sahebkar A (2018a) Effects of atorvastatin on myocardial oxidative and nitrosative stress in diabetic rats. Comp Clin Pathol 27:1–7CrossRefGoogle Scholar
  38. Yaribeygi H, Mohammadi MT, Rezaee R, Sahebkar A (2018b) Crocin improves renal function by declining Nox-4, IL-18, and p53 expression levels in an experimental model of diabetic nephropathy. J Cell Biochem 119:6080–6093CrossRefGoogle Scholar
  39. Yaribeygi H, Mohammadi MT, Sahebkar A (2018c) PPAR-α agonist improves hyperglycemia-induced oxidative stress in pancreatic cells by potentiating antioxidant defense system. Drug Res 68:355–360CrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Ltd., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Chronic Kidney Disease Research CenterShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Department of Physiology and Biophysics, School of MedicineBaqiyatallah University of Medical SciencesTehranIran
  3. 3.Life Sciences Research DivisionAnti-Doping Laboratory QatarDohaQatar
  4. 4.Neurogenic Inflammation Research CenterMashhad University of Medical SciencesMashhadIran
  5. 5.Biotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran
  6. 6.School of PharmacyMashhad University of Medical SciencesMashhadIran

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