PPAR-α agonist fenofibrate potentiates antioxidative elements and improves oxidative stress of hepatic cells in streptozotocin-induced diabetic animals
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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.
KeywordsOxidative 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.
- Aebi H (1984)  Catalase in vitro. In: Methods enzymol, vol 105. Elsevier, pp 121–126Google Scholar
- 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
- 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
- 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
- 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
- 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. https://doi.org/10.1016/j.atherosclerosis.2013.06.026 CrossRefGoogle Scholar
- 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. https://doi.org/10.1016/j.phrs.2015.12.001 CrossRefGoogle Scholar
- 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. https://doi.org/10.1186/s12916-017-0787-7 CrossRefGoogle Scholar
- 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
- 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: https://doi.org/10.1016/j.phrs.2017.12.030
- 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
- 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
- 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