Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20171085Keywords:
Adipokines, Diacerein, Non-alcoholic steatohepatitis, Pro-inflammatory cytokines, RatAbstract
Background: Non-alcoholic steatohepatitis (NASH) is considered as a progressive liver disease, so effective therapies are needed to ameliorate hepatic steatosis, inflammation and fibrosis, and to prevent the progression to cirrhosis and hepatocellular carcinoma. Diacerein is an anti-inflammatory drug that inhibits the synthesis and activity of pro-inflammatory cytokines. The present study was designed to investigate the effect of diacerein on pro-inflammatory cytokines as well as adipokines involved in diet-induced NASH rat model.
Methods: Thirty-two adult male rats were divided into four groups: control, diacerein-treated, NASH-untreated and NASH+diacerein-treated groups. NASH was induced by feeding rats with high-fat and high-cholesterol diet for 12 weeks. Body weight, liver weight, fasting blood glucose and insulin levels for estimation of insulin resistance, blood lipids, alanine transaminase, and aspartate aminotransferase were evaluated. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), adiponectin, visfatin and leptin were also detected. Histopathological examination of liver sections was performed.
Results: Diacerein significantly reduced liver weight, fasting blood glucose, insulin level, transaminases and ameliorates insulin resistance with favourable effects on blood lipids. These results were accompanied with a significant reduction in serum levels of TNF-α, IL-1β, IL-6, and visfatin, while, adiponectin was significantly increased and leptin was insignificantly affected. Liver sections revealed that diacerein reduced steatosis and lobular inflammatory grades.
Conclusions: These data suggest that diacerein administration may have a potential usefulness in the prevention of NASH as a possible result of inhibition of pro-inflammatory cytokines and the beneficial effects on adipokines especially adiponectin and visfatin.
References
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274-285.
Huang YY, Gusdon AM, Qu S. Nonalcoholic fatty liver disease: molecular pathways and therapeutic strategies. Lipids in Health and Disease. 2013;12:171.
Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147:577-94.
Jamali R, Arj A, Razavizade M, Aarabi MH. Prediction of nonalcoholic fatty liver disease via a novel panel of serum adipokines. Medicine. 2016;95(5):2630.
Casoinic F, Sampelean D, Buzoianu AD, Hancu N, Baston D. Serum levels of cytokines and adipokines in patients with non-alcoholic steatohepatitis and type 2 diabetes mellitus. HVM Bioflux. 2016;8(2):77-84.
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;8:76538.
Zhang W, Wang LW, Wang LK, Li X, Zhang H, Luo LP, et al. Betaine protects against high-fat-diet induced liver injury by inhibition of high-mobility group box 1 and Toll-like receptor 4 expression in rats. Dig Dis Sci. 2013;58:3198-3206.
Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lütjohann D, et al Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology. 2008;48:474-86.
Pasin JS, Ferreira AP, Saraiva AL, Ratzlaff V, Andrighetto R, Tomazetti J, et al. Diacerein decreases TNF-alpha and IL-1beta levels in peritoneal fluid and prevents Baker's yeast-induced fever in young rats. Inflamm Res. 2010;59(3):189-96.
Ramos-Zavala MG, González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, González-López R, Santiago-Hernández NJ. Effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes: a randomized clinical trial. Diabetes Care. 2011;34(7):1591-4.
Pavelka K, Bruye`re O, Cooper C, Kanis JA, Leeb BF, Maheu E, et al. Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO. Drugs Aging. 2016;33:75-85.
Jain A, Singh R, Singh S, Singh S. Diacerein protects against iodoacetate-induced osteoarthritis in the femorotibial joints of rats. J Biomed Res. 2015;29(5):405-13.
Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol. 1969;22(2):158-61.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-9.
Friedewald WT, Levi RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the ultracentrifuge. Clin Chem. 1972;18(6):499-502.
Brunt EM, Janney CG, Bisceglie AMDi, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol.1999;94(9):2467-74.
McCullough AJ. Epidemiology of the metabolic syndrome in USA. J Dig Dis. 2011;12:333-40.
Teratani T, Tomita K, Suzuki T. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology. 2012;142:152-64.
Lee Y, Sutedja D, Wai C, Dan Y, et al. Randomized controlled pilot study of entoxifylline in patients with non-alcoholic steatohepatitis (NASH). Hepatol Int. 2008;2:196-201.
Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147-52.
Gustafson B. Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb. 2010;17:332-41.
Moore AR, Greenslade KJ, Alam CA, Willoughby DA. Effects of diacerhein on granuloma induced cartilage breakdown in the mouse. Osteoarthritis Cartilage. 1998;6(1):19-23.
Tobar N, Oliveira AG, Guadagnini D, Bagarolli RA, Rocha GZ, Araujo TG. et al. Diacerhein improves glucose tolerance and insulin sensitivity in mice on a high-fat diet. Endocrinology. 2011;152:4080-93.
Villar MM, Martínez-Abundis E, Preciado-Márquez RO, González-Ortiz M. Effect of diacerein as an add-on to metformin in patients with type 2 diabetes mellitus and inadequate glycemic control. Arch Endocrinol Metab. 2017;13.
Borst SE. The role of TNF-alpha in insulin resistance. Endocrine. 2004;23:177-82.
Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor-α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55(3):415-24.
Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343-50.
Mas E, Danjoux M, Garcia V, Carpentier S, Ségui B, Levade T. IL-6 Deficiency Attenuates Murine Diet-Induced Non-Alcoholic Steatohepatitis. PLoS ONE 2009;4(11):7929.
Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008;103(6):1372-79.
Ota T, Takamura T, Kurita S, Matsuzawa N, Kita Y, Uno M, Akahori H, et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology. 2007;132(1):282-93.
Kamari Y, Shaish A, Vax E, Shemesh S, Kandel-Kfir M, Arbel Y, et al. Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J Hepatol. 2011;55(5):1086-94.
Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, et al. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology. 2010;51:511-22.
Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. Journal of hepatology. 2007;47(4):556-64.
Xu A, Wang Y, Keshaw H, Xu LY, Lam KSL, Cooper GJS. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clinical Investigation 2003;112(1):91-100.
Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, et al. Adiponectin protects LPS‐induced liver injury through modulation of TNF‐α in KK‐Ay obese mice. Hepatology. 2004;40(1):177-84.
López-Bermejo A, Chico-Julià B, Fernàndez-Balsells M, Recasens M, Esteve E, Casamitjana R, et al. Serum visfatin increases with progressive β-cell deterioration. Diabetes. 2006;55(10):2871-5.
Esteghamati A, Morteza A, Zandieh A, Jafari S, Rezaee M, Nakhjavani M, et al. The value of visfatin in the prediction of metabolic syndrome: a multi-factorial analysis. Journal of cardiovascular translational research. 2012;5(4):541-6.
de Boer JF, Bahr MJ, Böker KH, Manns MP, Tietge UJ. Plasma levels of PBEF/Nampt/visfatin are decreased in patients with liver cirrhosis. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2009;296(2):196-201.
Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia 2016;59(1):30-43.
Aller R, Izaola O, Ruiz-Rebollo L, Pacheco D, de Luis DA. Predictive factors of non-alcoholic steatohepatitis: relationship with metabolic syndrome. Nutr Hosp 2015;31(6):2496-502.
