THE ROLE OF CANNABINOID RECEPTOR 1 IN DEVELOPMENT OF OXIDATIVE/NITROSATIVE STRESS IN MICE WITH NON-ALCOHOLIC FATTY LIVER DISEASE
Abstract
Abstract
Introduction: Non-Alcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome. It represents a spectrum of disease ranging from steatosis, non-alcoholic steatohepatitis (NASH), that may progress to fibrosis, cirrhosis and eventually hepatocellular carcinoma.
Aim: The aim of study was to investigate the influence of cannabinoid receptor subtype 1 (CB1) blockade on intensity of oxidative/nitrosative stress in liver of mice with NAFLD. We therefore used rimonabant, selective CB1 antagonist.
Material and methods: Male mice C57BL/6 (n=28) were divided into following groups: 1. Control group - fed with control chow diet 20 weeks (C group; n=7), 2. Group fed with high saturated fat diet 20 weeks (HF group; n=7), 3. Group fed with standard chow diet and treated with rimonabant after 18 weeks (R group; n=7), 4. Group fed with high saturated fat diet and treated with rimonabant after 18 weeks (HFR group; n=7). The activity of liver transaminases was measured in serum. Concentrations of malondialdehyde (MDA), nitrites and nitrates (NOx), including the activity of superoxide dismutase (SOD), copper/zinc superoxide dismutase (Cu/ZnSOD) and manganese superoxide dismutase (MnSOD) were measured in the liver.
Results: Rimonabant induced decrease in liver transaminase activity in R group compared to C group (p˂0.01). Similar results were observed in HFR group compared to HF group (p˂0.01). Concentrations of MDA and NOx in HFR were lower compared to control (p˂0.01). We found decrease in SOD, Cu/ZnSOD and MnSOD activities in HFR group compared to HF group (p˂0.01).
Conclusion: According to the results of this study it can be concluded that blockade of CB1 receptors causes useful effects in treatment of NAFLD. Rimonabant reduced hepatocellular injury decreasing the activity of liver transaminases in serum. Reduction of oxidative/nitrosative stress and lipid peroxidation may also contribute to protective effects of rimonabant, shown as decrease in MDA concentration.
Keywords: NAFLD, CB1 receptors, endocannabinoid system, rimonabant, oxidative/nitrosative stress
References
Tiniakos DG, Vos MB, Brunt EM. Nonacloholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010; 5:145-171.
Buzzeti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016; 65(8):1038-1048.
Jorgačević B, Mladenović D, Ninković N, Prokić V, Stanković MN, Aleksić V et al. Dynamics of oxidative/nitrosative stress in mice with methionine-choline-deficient diet-induced nonalcoholic fatty liver disease. Hum Exp Toxicol. 2014; 33 (7):701-709.
Jennie Ka CL, Xiang Z, Jun Y. Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances. J Pathol. 2017; 241:36-44.
Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med. 2012; 52:59-69.
Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci. 2015; 16(11):26087-26124.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clinica Chimica Acta. 2011; 412:1297-1305.
Jorgačević B, Vučević D, Đuričić I, Šobajić S, Mladenović D, Vesković M et al. The effect of cannabinoid receptor 1 blockade on hepatic free fatty acid profile in mice with nonalcoholic fatty liver disease. Chem Phys Lipids. 2017; 204:85-93.
Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. Endocannabinoids in liver disease. Hepatology 2011; 53:346-355.
Mallat A, Teixera-Clerc F, Deveaux V, Manin S, Lotersztajn. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Br J Pharmacol. 2011; 163:1432-1440.
Hanus L, Avraham Y, Ben-Shushan D, Zolotarev O, Berry EM, Mechoulam R. Short-term fasting and prolonged semistarvation have opposite effects on 2-AG levels in mouse brain. Brain Res. 2003; 983:144-151.
Bermudez-Silva FH, Cardinal D, Cota D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J Psychopharmacol. 2012; 26:114-124.
Vettor R, Pagano C. The role of the endocannabinoid system in lipogenesis and fatty acid metabolism. Best Pract Res Clin Endocrinol Metab. 2009; 23:51-63.
Romero-Zerbo SY, Bermudez-Silva FJ. Cannabinoids, eating behaviour, and energy homeostasis. Drug Test Anal. 2014; 6:52-58.
Di Marzo V, Despres JP. CB1 antagonists for obesity-what lessons have we learnt from rimonabant? Nat Rev Endocrinol. 2009; 5:633-638.
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951; 193:265-275.
Girotti M, Khan N, McLellan B. Early measurement of systemic lipid peroxidation products in the plasma of major blunt trauma patients. J Trauma. 1991; 31:32-35.
Hibbs JB, Taintor R, Vavrin Z, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1989; 157:87-94.
Sun M, Zigman S. An improved spectrophotometric assay for superoxide dismutase based on epinephrine autooxidation. Anal Biochem. 1978; 90:81-90.
Fakhoury-Sayegh N, Trak-Smayra V, Khazzaka A, Esseily F, Obeid O, Lahoud-Zouein M, Younes H. Characteristics of nonalcoholic fatty liver disease induced in wistar rats following four different diets. Nutr Res Pract. 2015; 9(4):350-357.
Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet-Trillou C, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007; 46:122–129.
Petta S, Muratore C, Craxi A. Non-alcoholic fatty liver disease pathogenesis: The present and the future. Dig Liver Dis. 2009; 41:615-625.
Videla LA. Oxidative stress signaling underlying liver disease and hepatoprotective mechanism. World J Hepatol. 2009; 1(1):72-78.
Fakhoury-Sayegh N, Trak-Smayra V, Khazzaka A, Esseily F, Obeid O, Lahoud-Zouein M et al. Characteristics of nonalcoholic fatty liver disease induced in wistar rats following four different diets. Nutr Res Pract. 2015; 9(4):350–357.
Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in non-alcoholic fatty liver disease: Mechanism and pathopysiological role. Clin Res Hepatol Gastroenerol. 2011; 35:630-637.
Jourdan T, Djaouti L, Demizieux L, Gresti J, Vergès B, Degrace P. CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes. 2010; 59:926–934.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365:1389–1397.
Hussien NI, El-Kerdasy HI, Ibrahim ME. Protective effect of rimonabant, a canabinoid receptor 1 antagonist, on non-alcoholic fatty liver disease in a rat model through modulation of the hepatic espression of activin A and follistatin. Can J Physiol Pharmacol. 2017; 95(12):1433-1441.
Pankaj GJ, Sanjay SJ. Isolation, characterization and hypolipidemic activity of ferulic acid in high-fat-diet-induced hyperlipidemia in laboratory rats. Excli J. 2016; 15: 599-613.
Hardwick RN, Fisher CD, Canet MJ, Lake AD, Cherrington NJ. Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos. 2010; 38:2293-2301.