Home >Current Issue
Volume: 9, Issue: 7, July, 2019
Concomitant administration of atorvastatin with N-acetylcysteine mitigates liver injury and steatosis in experimental non-alcoholic fatty liver diseaseAuthor Affiliations
Although numerous efforts have been directed toward searching for new treatments against non-alcoholic fatty liver disease (NAFLD), there are no approved pharmacologic agents up to date. This study evaluates the therapeutic effect of concomitant administration of atorvastatin (ATO) and N-Acetylcysteine (NAC) with/without diet control. Nine groups of rats were divided into: normal, rats fed on high-fat diet for 12 weeks (NAFLD-HFD model), HFD-rats switched to regular diet (NAFLD-RD model), NAFLD-HFD or -RD rats treated with either ATO or NAC orally with 30 or 500 mg/kg/day, respectively, or both for 8 weeks. NAFLD-HFD rats exhibited remarkable steatosis with lobular inflammation, hepatocytes vacuolation, and fibrosis, as well as significant changes in lipid profile, oxidative stress, and adipocytokines and these manifestations were less prominent in the HFD-RD group. ATO and NAC combination with diet control has the added benefits on ameliorating lipid levels, liver enzymes, oxidative stress, hepatic steatosis (9.01% ± 1.66% vs. 13.21% ± 2.20% for ATO and 25.60% ± 2.11% for NAC), inflammation, hepatocyte vacuolation, and fibrosis versus each drug separately. Conclusion: ATO and NAC concomitant therapy has a greater effect on NAFLD as compared to monotherapy and is recommended for further investigation in clinical trials.
Copyright: The Author(s). This is an open access article distributed under the Creative Commons Attribution Non-Commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ali MH, Messiha BA, Abdel-Latif, HA. Protective effect of ursodeoxycholic acid, resveratrol, and N-acetylcysteine on nonalcoholic fatty liver disease in rats. Pharm Biol, 2016; 54:1198−208. https://doi.org/10.3109/13880209.2015.1060247
Amacher DE, Schomaker SJ, Aubrecht J. Development of blood biomarkers for drug-induced liver injury: an evaluation of their potential for risk assessment and diagnostics. Mol Diagn Ther, 2013; 17:343−54. https://doi.org/10.1007/s40291-013-0049-0
Araki S, Dobashi K, Kubo K, Yamamoto Y, Asayama K, Shirahata A. N-acetylcysteine attenuates TNF-alpha induced changes in secretion ofinterleukin-6, plasminogen activator inhibitor-1 and adiponectin from 3T3-L1adipocytes. Life Sci, 2006; 79:2405−12. https://doi.org/10.1016/j.lfs.2006.08.004
Baumgardner JN, Shankar K, Hennings L, Badger TM, Ronis MJ. A new model for non-alcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high polyunsaturated fat diet. Am J Physiol Gastrointest Liver Physiol, 2008; 294:G27−38. https://doi.org/10.1152/ajpgi.00296.2007
Berry A, Bellisario V, Panetta P, Raggi C, Magnifico MC, Arese M, Cirulli F. Administration of the antioxidant N-acetylcysteine in pregnant mice has long-term positive effects on metabolic and behavioral endpoints of male and female offspring prenatally exposed to a high-fat diet. Front Behav Neurosci, 2018; 12:48. https://doi.org/10.3389/fnbeh.2018.00048
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology, 2012; 142:1592−609. https://doi.org/10.1053/j.gastro.2012.04.001
Dajani A, Abu Hammour A. Treatment of nonalcoholic fatty liver disease: where do we Stand? An Overview. Saudi J Gastroenterol, 2016; 22:91−104.
Dunzendorfer S, Rothbucher D, Schratzberger P, Reinisch N, Kahler CM, Wiedermann CJ. Mevelonate-dependent inhibition of transendothelial migration and chemotaxis of human peripheral blood neutrophils by pravastatin. Circ Res, 1997; 81:963−69. https://doi.org/10.1161/01.RES.81.6.963
Foster T, Matthew J, Budoff SS, Naser A, Craig G, Alan D, Guerci MD. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study Randomized Clinical Trial. Am J Gastroenterol, 2011; 106:71−7.
Galicia-Moreno M, Rodríguez-Rivera A, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Muriel P. N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress. Eur J Gastroenterol Hepatol, 2009; 21:908−14. https://doi.org/10.1097/MEG.0b013e32831f1f3a
Giby VG, Ajith TA. Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol, 2014; 6:570−79. https://doi.org/10.4254/wjh.v6.i8.570
Hernández-Guerra M, García-Pagán JC, Turnes J, Bellot P, Deulofeu R, Abraldes JG, Bosch J. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology, 2006; 43:485−91. https://doi.org/10.1002/hep.21080
Khoshbaten M, Aliasgarzadeh A, Masnadi K, Tarzamani MK, Farhang S, Babaei H, Kiani J, Zaare M, Najafipoor F. N-acetylcysteine improves liver function in patients with non-alcoholic Fatty liver disease. Hepat Mon, 2010; 10:12−6. https://doi.org/10.4103/1319-3767.65197
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 2005; 41:1313−21. https://doi.org/10.1002/hep.20701
Ma Y, Gao M, Liu D. N-acetylcysteine protects mice from high fat diet-induced metabolic disorders. Pharm Res, 2016; 33:2033−42. https://doi.org/10.1007/s11095-016-1941-1
Martın-Castillo A, Castells MT, Ada'nez G, Sa'nchez Polo, MT Pe'rez BG, Ayala I. Effect of atorvastatin and diet on non-alcoholic fatty liver disease activity score in hyperlipidemic chickens. Biomed Pharmacother, 2010; 64:275−81. https://doi.org/10.1016/j.biopha.2009.06.003
Mäuser W, Perwitz N, Meier B, Fasshauer M, Klein J. Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function, and inhibition of glucose uptake. Eur J Pharmacol, 2007; 564:37−46. https://doi.org/10.1016/j.ejphar.2007.02.024
Nseir W, Mahamid M. Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review. Curr Atheroscler Rep, 2013; 15:305. https://doi.org/10.1007/s11883-012-0305-5
Pereira-Filho G, Ferreira C, Schwengber A, Marroni C, Zettler C, Marroni N. Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats. Arq Gastroenterol, 2008; 45:156−62. https://doi.org/10.1590/S0004-28032008000200013
Roglans N, Sanguino E, Peris C, Alegret M, Vázquez M, Adzet T, Díaz C, Hernández G, Laguna JC, Sánchez RM. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma non esterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther, 2002; 302:232−39. https://doi.org/10.1124/jpet.302.1.232
Samuhasaneeto S, Thong-Ngam D, Kulaputana O, Patumraj S, Klaikeaw N. Effects of N-acetylcysteine on oxidative stress in rats with non-alcoholic steatohepatitis. J Med Assoc Thai, 2007; 90:788−97.
Souza MR, DinizMde F, Medeiros-Filho JE, Araújo MS. Metabolic syndrome an drisk factors for non-alcoholic fatty liver disease. Arq de Gastroenterol, 2012; 49:89−96. https://doi.org/10.1590/S0004-28032012000100015
Stärkel P, Sempoux C, Leclercq I, Herin M, Deby C, Desager JP, Horsmans Y. Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol, 2003; 39:538−46. https://doi.org/10.1016/S0168-8278(03)00360-X
Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol, 2015; 21:3777−85. https://doi.org/10.3748/wjg.v21.i13.3777
Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev, 2011; 19:CD004816. https://doi.org/10.1002/14651858.CD004816.pub4
Tsukamoto H. Oxidative stress, antioxidants, and alcoholic liver fibrogenesis. Alcohol, 1993; 10:465−7. https://doi.org/10.1016/0741-8329(93)90066-W
Uzun MA, Koksal N, Kadioglu H, Gunerhan Y, Aktas S, Dursun N, Sehirli AO. Effects of N-acetylcysteine on regeneration following partial hepatectomy in rats with nonalcoholic fatty liver disease. Surg Today, 2009; 39:592−97. https://doi.org/10.1007/s00595-008-3930-4
Wang W, Zhao C, Zhou J, Zhen Z, Wang Y, Shen C. Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis related liver fibrosis. PLoS One, 2013; 8:e76538. https://doi.org/10.1371/journal.pone.0076538
Zulet MA, Barber A, Garcin H, Higueret P, Martinez JA. Alterations in carbohydrate and lipid metabolism induced by a diet rich in coconut oil and cholesterol in a rat model. J Am Coll Nutr, 1999; 1:3642. https://doi.org/10.1080/07315724.1999.10718825