Effect of Canagliflozin, an SGLT2 Inhibitor, in Comparison with Atorvastatin on Dexamethasone-Induced Hepatic Steatosis in Albino Rats

Author(s): Eman I. Ahmed*, Amany M. Shaaban, Abdel Karim M. Abdel Latif

Journal Name: Current Drug Therapy

Volume 15 , Issue 3 , 2020


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Abstract:

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease that is considered to be the most common liver disease all over the world. It causes metabolic and hepatic damage that can progress to cirrhosis and hepatocellular carcinoma.

Objective: Our research pointed to study the preventive effects of Canagliflozin (CANA) in comparison with Atorvastatin (ATO) as well as the combination of both on the development of experimental hepatic steatosis and dyslipidemia.

Methods: Animals were grouped as control group; Dexamethasone (DEX) group; ATO/DEX treated group; CANA/DEX treated group and ATO+CANA/DEX treated group.

Results: Significant elevations were observed in GSH, SOD and CAT activities, while highly significant decreases were observed in serum GOT, GPT, ALP, urea, blood glucose, CK-MB, LDH, T.G, T.C, MDA and P.C levels in the treated groups as compared to DEX group during experimental periods. Also, significant reductions in SGPT, SGOT, ALP, CK-MB, LDH, T.C and T.G levels were observed in CANA/DEX group as compared to ATO/DEX group. All these results were confirmed with histopathological findings where the severe damages and fatty degeneration in both kidney and liver tissues that developed by DEX administration were resolved by administration of ATO alone or in combination with CANA.

Conclusion: These results indicate that CANA was as effective as ATO or a combination of both in reducing dyslipidemia and hepatic steatosis. The antioxidant and hypolipidemic effects of CANA may be responsible for the beneficial effects.

Keywords: Hepatic steatosis, canagliflozin, atorvastatin, dexamethasone, dyslipidemia, inhibitor.

[1]
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346(16): 1221-31.
[http://dx.doi.org/10.1056/NEJMra011775] [PMID: 11961152]
[2]
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(3): 274-85.
[http://dx.doi.org/10.1111/j.1365-2036.2011.04724.x] [PMID: 21623852]
[3]
Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37(5): 1202-19.
[http://dx.doi.org/10.1053/jhep.2003.50193] [PMID: 12717402]
[4]
Lettéron P, Brahimi-Bourouina N, Robin MA, Moreau A, Feldmann G, Pessayre D. Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation. Am J Physiol 1997; 272(5 Pt 1): G1141-50.
[PMID: 9176224]
[5]
Ji G, Zhao X, Leng L, Liu P, Jiang Z. Comparison of dietary control and atorvastatin on high fat diet induced hepatic steatosis and hyperlipidemia in rats. Lipids Health Dis 2011; 10(1): 23.
[http://dx.doi.org/10.1186/1476-511X-10-23] [PMID: 21269482]
[6]
Seif El-Din SH, El-Lakkany NM, El-Naggar AA, et al. Effects of rosuvastatin and/or β-carotene on non-alcoholic fatty liver in rats. Res Pharm Sci 2015; 10(4): 275-87.
[PMID: 26600855]
[7]
Chong LW, Hsu YC, Lee TF, et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol 2015; 15(1): 22.
[http://dx.doi.org/10.1186/s12876-015-0248-8] [PMID: 25886887]
[8]
Kimura Y, Hyogo H, Yamagishi S, et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010; 45(7): 750-7.
[http://dx.doi.org/10.1007/s00535-010-0203-y] [PMID: 20112031]
[9]
Zhang N, Huan Y, Huang H, Song GM, Sun SJ, Shen ZF. Atorvastatin improves insulin sensitivity in mice with obesity induced by monosodium glutamate. Acta Pharmacol Sin 2010; 31(1): 35-42.
[http://dx.doi.org/10.1038/aps.2009.176] [PMID: 20023693]
[10]
Miyaki T, Nojiri S, Shinkai N, et al. Pitavastatin inhibits hepatic steatosis and fibrosis in non-alcoholic steatohepatitis model rats. Hepatol Res 2011; 41(4): 375-85.
[http://dx.doi.org/10.1111/j.1872-034X.2010.00769.x] [PMID: 21276150]
[11]
Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care 2015; 38(12): 2344-53.
[http://dx.doi.org/10.2337/dc15-0642] [PMID: 26604280]
[12]
Honda Y, Imajo K, Kato T, et al. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS One 2016; 11(1)e0146337
[http://dx.doi.org/10.1371/journal.pone.0146337] [PMID: 26731267]
[13]
Obata A, Kubota N, Kubota T, et al. Tofogliflozin improves insulin resistance in skeletal muscle and accelerates lipolysis in adipose tissue in male mice. Endocrinology 2016; 157(3): 1029-42.
[http://dx.doi.org/10.1210/en.2015-1588] [PMID: 26713783]
[14]
Komiya C, Tsuchiya K, Shiba K, et al. Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction. PLoS One 2016; 11(3)e0151511
[http://dx.doi.org/10.1371/journal.pone.0151511] [PMID: 26977813]
[15]
Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013; 382(9896): 941-50.
[http://dx.doi.org/10.1016/S0140-6736(13)60683-2] [PMID: 23850055]
[16]
Vinodraj K, Nagendra Nayak IM, Rao JV, et al. Comparison of the efficacy of liraglutide with pioglitazone on dexamethasone induced hepatic steatosis, dyslipidemia and hyperglycaemia in albino rats. Indian J Pharmacol 2015; 47(2): 181-4.
[http://dx.doi.org/10.4103/0253-7613.153426] [PMID: 25878378]
[17]
Sherwin JE. Liver function. In: Kaplan LA, Pesce AJ, eds. Clinical Chemistry, theory, analysis, and correlation.. St Louis: Mosby 1984; 420-38.
[18]
Belfield A, Goldberg D. Colorimetric determination of alkaline phosphatase activity. Enzyme 1971; 12: 561-6.
[http://dx.doi.org/10.1159/000459586] [PMID: 5169852]
[19]
Tietz NW. Textbook of Clinical Chemistry. W.B.Saunders Company: Philadelphia 1986; pp. 1271-81.
[20]
Tietz NW. Clinical guide to Laboratory tests. 2nd ed. 1990; p. 566.
[21]
Würzburg U, Hennrich N, Orth HD, et al. Quantitative determination of creatine kinase isoenzyme catalytic concentrations in serum using immunological methods. J Clin Chem Clin Biochem 1977; 15(3): 131-7.
[http://dx.doi.org/10.1515/cclm.1977.15.1-12.131]
[22]
Henry RJ. Colorimetric determination of lactic dehydrogenase. Clinical chemistry: principles and techniques 1974; 819-31.
[23]
Roeschlau P, Bernt E, Gruber JW. Enzymatic determination of total cholesterol in serum. Z Klin Chem Klin Biochem 1974; 12: 403-7.
[24]
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95(2): 351-8.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[25]
Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 1994; 233: 357-63.
[http://dx.doi.org/10.1016/S0076-6879(94)33041-7] [PMID: 8015470]
[26]
Minami M, Yoshikawa H. A simplified assay method of superoxide dismutase activity for clinical use. Clin Chim Acta 1979; 92(3): 337-42.
[http://dx.doi.org/10.1016/0009-8981(79)90211-0] [PMID: 436274]
[27]
Aebi H. Catalase.In: Bergmeyer H U eds. Methods of Enzymatic Analysis 2nd ed Verlag Chemie Weinheim, Germany 1983; 273-7.
[28]
Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61: 882-8.
[PMID: 13967893]
[29]
Jia Y, Viswakarma N, Fu T, et al. Conditional ablation of mediator subunit MED1 (MED1/PPARBP) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone-induced hepatic steatosis. Gene Expr 2009; 14(5): 291-306.
[http://dx.doi.org/10.3727/105221609788681213] [PMID: 19630272]
[30]
Kumar VR, Inamdar MN. Nayeemunnisa, Viswanatha GL. Protective effect of lemongrass oil against dexamethasone induced hyperlipidemia in rats: possible role of decreased lecithin cholesterol acetyl transferase activity. Asian Pac J Trop Med 2011; 4(8): 658-60.
[http://dx.doi.org/10.1016/S1995-7645(11)60167-3] [PMID: 21914547]
[31]
Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician 1999; 59(8): 2223-30.
[PMID: 10221307]
[32]
Muriel P, González P. Liver damage induced by acute cholestasis in the rat is ameliorated partially by L-arginine. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1998; 120(3): 421-4.
[http://dx.doi.org/10.1016/S0742-8413(98)10018-X] [PMID: 9827059]
[33]
Nishimura N, Kitade M, Noguchi R, et al. Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka Long-Evans Tokushima fatty rats. J Gastroenterol 2016; 51(12): 1141-9.
[http://dx.doi.org/10.1007/s00535-016-1200-6] [PMID: 27025708]
[34]
Ou JM, Zhang XP, Wu CJ, Wu DJ, Yan P. Effects of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis. J Zhejiang Univ Sci B 2012; 13(11): 919-31.
[http://dx.doi.org/10.1631/jzus.B1100351] [PMID: 23125085]
[35]
Maheshwari RA, Sailor GU, Patel L, Balaraman R. Amelioration of cisplatin-induced nephrotoxicity by statins. Indian J Pharmacol 2013; 45(4): 354-8.
[http://dx.doi.org/10.4103/0253-7613.115016] [PMID: 24014910]
[36]
Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol 2017; 28(1): 368-75.
[http://dx.doi.org/10.1681/ASN.2016030278] [PMID: 27539604]
[37]
Hyogo H, Tazuma S, Arihiro K, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008; 57(12): 1711-8.
[http://dx.doi.org/10.1016/j.metabol.2008.07.030] [PMID: 19013295]
[38]
Kabel AM, Abd Elmaaboud MA, Albarraq AA. Ameliorative potential of omega 3 fatty acids and HMG-CoA reductase inhibitors on experimentally-induced non-alcoholic steatohepatitis. Prostaglandins Leukot Essent Fatty Acids 2015; 96: 1-9.
[http://dx.doi.org/10.1016/j.plefa.2014.12.003] [PMID: 25541279]
[39]
Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol 2011; 46(1)(Suppl. 1): 63-9.
[http://dx.doi.org/10.1007/s00535-010-0311-8] [PMID: 20844903]
[40]
Marie MAS, Arafa NMS, Alazimi SAM. Effect of canagliflozin or metformin on metabolic disorders in obese diabetic rats. Afr J Pharm Pharmacol 2015; 9(46): 1071-9.
[http://dx.doi.org/10.5897/AJPP2015.4455]
[41]
Spahis S, Delvin E, Borys JM, Levy E. Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis. Antioxid Redox Signal 2017; 26(10): 519-41.
[http://dx.doi.org/10.1089/ars.2016.6776]
[42]
Machado MV, Ravasco P, Jesus L, et al. Blood oxidative stress markers in non-alcoholic steatohepatitis and how it correlates with diet. Scand J Gastroenterol 2008; 43(1): 95-102.
[http://dx.doi.org/10.1080/00365520701559003] [PMID: 18938777]
[43]
Murrow JR, Sher S, Ali S, et al. The differential effect of statins on oxidative stress and endothelial function: atorvastatin versus pravastatin. J Clin Lipidol 2012; 6(1): 42-9.
[http://dx.doi.org/10.1016/j.jacl.2011.08.006] [PMID: 22264573]
[44]
Tahara A, Kurosaki E, Yokono M, et al. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol 2014; 66(7): 975-87.
[http://dx.doi.org/10.1111/jphp.12223] [PMID: 24533859]
[45]
Shiba K, Tsuchiya K, Komiya C, et al. Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. Sci Rep 2018; 8(1): 2362.
[http://dx.doi.org/10.1038/s41598-018-19658-7] [PMID: 29402900]
[46]
Eken H, Ozturk H, Ozturk H, Buyukbayram H. Dose-related effects of dexamethasone on liver damage due to bile duct ligation in rats. World J Gastroenterol 2006; 12(33): 5379-83.
[http://dx.doi.org/10.3748/wjg.v12.i33.5379] [PMID: 16981272]
[47]
Mathai P, Nayak N, Rao M, et al. Comparison of the efficacy of sitagliptin with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats. Int J Basic Clin Pharmacol 2017; 4(1): 60-4.
[http://dx.doi.org/10.5455/2319-2003.ijbcp20150209]
[48]
Hussein AJ, Majeed MF, Abbas AS. Histopathological study of some organs after long-term treatment with dexamethasone in male rabbits. Sci J Uni Zakho 2014; 2(1): 39-48.
[http://dx.doi.org/10.25271/2014.2.1.131]


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2020
Published on: 14 October, 2020
Page: [274 - 282]
Pages: 9
DOI: 10.2174/1574885514666191007094424

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