Uloga kanabinoidnih CB1 receptora u razvoju oksidativnog/nitrozativnog stresa u toku nealkoholne masne bolesti jetre kod miševa
Sažetak
Uvod: Nealkoholna masna bolest jetre (eng. Non-Alcoholic Fatty Liver Disease, NAFLD) je hepatična manifestacija metaboličkog sindroma koja se ispoljava širokim spektrom bolesti jetre, od steatoze do nealkoholnog steatohepatitisa (engl. Non-Alcoholic Steatohepatitis, NASH), fibroze i ciroze jetre, sa mogućnošću razvoja hepatocelularnog karcinoma.
Cilj rada: Cilj istraživanja je da se ispita uticaj blokade CB1 kanabinoidnih receptora na intenzitet oksidativnog/nitrozativnog stresa u jetri miševa sa NAFLD. Zarad toga upotrebljen je rimonabant, selektivni antagonist CB1 receptora.
Materijal i metode: Mužjaci miševa C57BL/6 soja (n = 28) podeljeni su u sledeće grupe: 1) Kontrolna grupa - životinje na standardnoj ishrani, u trajanju od 20 nedelja (C grupa; n = 7); 2) Grupa životinja hranjenih dijetom bogatom mastima, u trajanju od 20 nedelja (HF grupa; n = 7); 3) Grupa životinja na standardnoj ishrani, tretirana rimonabantom nakon 18 nedelja (R grupa; n = 7) i 4) Grupa životinja hranjenih dijetom bogatom mastima, tretirana rimonabantom nakon 18 nedelja (HFR grupa; n = 7). Nakon 20 nedelja merena je aktivnost transaminaza u serumu. U jetri su određene koncentracije malondialdehida (MDA), nitrita i nitrata (NOx) i aktivnosti ukupne superoksid dismutaze (SOD), bakar/cink-superoksid dismutaze (Cu/ZnSOD) i mangan-superoksid dismutaze (MnSOD).
Rezultati: Primena rimonabanta dovela je do smanjenja aktivnosti transaminaza u R grupi u odnosu na kontrolu, kao i u HFR grupi u odnosu na HF grupu (p < 0,01, respektivno). Koncentracija MDA i NOx u HFR grupi bila je snižena u poređenju sa HF grupom (p < 0,01). Aktivnosti ukupne SOD, Cu/ZnSOD i MnSOD u HFR grupi bile su statistički značajno smanjene u odnosu na HF grupu (p < 0,01).
Zaključak: Na osnovu rezultata studije može se zaključiti da blokada CB1 receptora ispoljava potencijalno korisne efekte u tretmanu NAFLD. Rimonabant je doveo do smanjenja stepena hepatocelularnog oštećenja, na šta ukazuje smanjena aktivnost transaminaza u serumu miševa. Primena rimonabanta dovela je do smanjenja intenziteta oksidativnog/nitrozativnog stresa i lipidne peroksidacije, što je pokazano smanjenjеm koncentracije MDA i NOx.
Ključne reči: NAFLD; CB1 receptori; endokanabinoidni sistem; rimonabant; oksidativni/nitrozativni stres
Reference
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.