Pharmacological Action of Atorvastatin and Metformin on Non-alcoholic
Fatty Liver Disease on an Experimental Model of Metabolic Syndrome

Castillo   Tomas   Augusto; María      de la Paz Scribano Parada; Micaela   Milagros   Rossi; Franco      Signorini; Ismael      Fonseca; María      del Carmen Baez

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in the world. It is known that there is a pathogenic relation between liver damage and the inflammatory and oxidative environment present in Metabolic Syndrome (MS).

Objective: To study the pharmacological action of atorvastatin and metformin in an experimental model of MS.

Methods: We used 40 male rats (Wistar) divided into the following groups: Control (A) (n=8), induced MS (B) (n=8), MS + atorvastatin treatment (C)(n=8), MS + metformin treatment (D) (n=8) and MS + combined treatment (E) (n=8). MS was induced by administering 10% fructose in drinking water for 45 days. Atorvastatin 0.035 mg/day/rat, metformin 1.78 mg/day/rat, and a combination of both drugs were administered for 45 days. Metabolic, oxidative (nitric oxide, myeloperoxidase and superoxide dismutase) and inflammatory (fibrinogen) parameters were determined. Histological sections of liver were analyzed by light microscopy.

Results: The glycemia, lipid profile and TG/HDL-C index were altered in MS group. After pharmacological treatment, metabolic parameters improve significantly in all treated groups. Inflammatory and oxidative stress biomarkers increase in MS. Treated groups showed an increase in NO bioavailability, no difference in MPO activity and an increase in fibrinogen. Atorvastatin showed a decrease in SOD while Metformin and combination treatment showed an increase in SOD compared to MS. In MS, we observed histological lesions consistent with NAFLD. However, after a combined treatment, we observed total regression of these lesions.

Conclusion: Our results showed that there is an important synergy between atorvastatin and metformin in improving liver involvement in MS.

Keywords: Non-alcoholic fatty liver disease, metabolic syndrome, atorvastatin, metformin, oxidative stress, inflammation.

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[1]
Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med.,  2018, 24(7), 908-922.
 [http://dx.doi.org/10.1038/s41591-018-0104-9] [PMID: 29967350]

[2]
Marino, L.; Jornayvaz, F.R. Endocrine causes of nonalcoholic fatty liver disease. World J. Gastroenterol.,  2015, 21(39), 11053-11076.
 [http://dx.doi.org/10.3748/wjg.v21.i39.11053] [PMID: 26494962]

[3]
Martín-Domínguez, V.; González-Casas, R.; Mendoza-Jiménez-Ridruejo, J.; García-Buey, L.; Moreno-Otero, R. Pathogenesis, diagnosis and treatment of non-alcoholic fatty liver disease. Rev. Esp. Enferm. Dig.,  2013, 105(7), 409-420.
 [http://dx.doi.org/10.4321/S1130-01082013000700006] [PMID: 24206551]

[4]
El-Kader, S.M.A.; El-Den Ashmawy, E.M.S. Non-alcoholic fatty liver disease: The diagnosis and management. World J. Hepatol.,  2015, 7(6), 846-858.
 [http://dx.doi.org/10.4254/wjh.v7.i6.846] [PMID: 25937862]

[5]
Farzanegi, P.; Dana, A.; Ebrahimpoor, Z.; Asadi, M.; Azarbayjani, M.A. Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): Roles of oxidative stress and inflammation. Eur. J. Sport Sci.,  2019, 19(7), 994-1003.
 [http://dx.doi.org/10.1080/17461391.2019.1571114] [PMID: 30732555]

[6]
Younes, R.; Bugianesi, E. A spotlight on pathogenesis, interactions and novel therapeutic options in NAFLD. Nat. Rev. Gastroenterol. Hepatol.,  2019, 16(2), 80-82.
 [http://dx.doi.org/10.1038/s41575-018-0094-6] [PMID: 30559444]

[7]
Fonseca, L.J.S.; Nunes-Souza, V.; Guedes, G.S.; Schettino-Silva, G.; Mota-Gomes, M.A.; Rabelo, L.A. Oxidative status imbalance in patients with metabolic syndrome: role of the myeloperoxidase/hydrogen peroxide axis. Oxid. Med. Cell. Longev.,  2014, 2014, 898501.
 [http://dx.doi.org/10.1155/2014/898501] [PMID: 25386227]

[8]
Pulli, B.; Ali, M.; Forghani, R.; Schob, S.; Hsieh, K.L.C.; Wojtkiewicz, G.; Linnoila, J.J.; Chen, J.W. Measuring myeloperoxidase activity in biological samples. PLoS One,  2013, 8(7), e67976.
 [http://dx.doi.org/10.1371/journal.pone.0067976] [PMID: 23861842]

[9]
Kato, Y. Neutrophil myeloperoxidase and its substrates: formation of specific markers and reactive compounds during inflammation. J. Clin. Biochem. Nutr.,  2016, 58(2), 99-104.
 [http://dx.doi.org/10.3164/jcbn.15-104] [PMID: 27013775]

[10]
Navarese, E.P.; Robinson, J.G.; Kowalewski, M.; Kołodziejczak, M.; Andreotti, F.; Bliden, K.; Tantry, U.; Kubica, J.; Raggi, P.; Gurbel, P.A. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: A systematic review and meta-analysis. JAMA,  2018, 319(15), 1566-1579.
 [http://dx.doi.org/10.1001/jama.2018.2525] [PMID: 29677301]

[11]
Oesterle, A.; Laufs, U.; Liao, J.K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res.,  2017, 120(1), 229-243.
 [http://dx.doi.org/10.1161/CIRCRESAHA.116.308537] [PMID: 28057795]

[12]
Cai, A.; Zhou, Y.; Li, L. Rho‐GTPase and atherosclerosis: pleiotropic effects of statins. J. Am. Heart Assoc.,  2015, 4(7), e002113.
 [http://dx.doi.org/10.1161/JAHA.115.002113] [PMID: 26124206]

[13]
Morantes-Caballero, J.A.; Londoño-Zapata, G.A.; Rubio-Rivera, M.; Pinilla-Roa, A.E. Metformina: más allá del control glucémico. Revista Médicas UIS,  2017, 30(1), 57-71.
 [http://dx.doi.org/10.18273/revmed.v30n1-2017005]

[14]
Viollet, B.; Guigas, B.; Garcia, N.S.; Leclerc, J.; Foretz, M.; Andreelli, F. Cellular and molecular mechanisms of metformin: An overview. Clin. Sci.,  2012, 122(6), 253-270.
 [http://dx.doi.org/10.1042/CS20110386] [PMID: 22117616]

[15]
Marshall, S.M. 60 years of metformin use: A glance at the past and a look to the future. Diabetologia,  2017, 60(9), 1561-1565.
 [http://dx.doi.org/10.1007/s00125-017-4343-y] [PMID: 28776085]

[16]
Jing, Y.; Wu, F.; Li, D.; Yang, L.; Li, Q.; Li, R. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol. Cell. Endocrinol.,  2018, 461, 256-264.
 [http://dx.doi.org/10.1016/j.mce.2017.09.025] [PMID: 28935544]

[17]
Balasubramanian, R.; Varadharajan, S.; Kathale, A.; Nagraj, L.M.; Periyandavar, I.; Nayak, U.P.; Sharma, A.; Bolmall, C.; Baliga, V.P. Assessment of the efficacy and tolerability of a fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg in diabetic dyslipidaemia in adult Indian patients. J. Indian Med. Assoc.,  2008, 106(7), 464-467.
 [PMID: 18975505]

[18]
Tousoulis, D.; Koniari, K.; Antoniades, C.; Miliou, A.; Noutsou, M.; Nikolopoulou, A.; Papageorgiou, N.; Marinou, K.; Stefanadi, E.; Stefanadis, C. Impact of 6 weeks of treatment with low-dose metformin and atorvastatin on glucose-induced changes of endothelial function in adults with newly diagnosed type 2 diabetes mellitus: A single-blind study. Clin. Ther.,  2010, 32(10), 1720-1728.
 [http://dx.doi.org/10.1016/j.clinthera.2010.09.007] [PMID: 21194594]

[19]
Renna, N.; Vázquez, M.; González, S.; Lama, C.; Cruzado, M.; Miatello, R. Expresión vascular de factores de transcripción proinflamatorios en un modelo de síndrome metabólico. Rev. Argent. Cardiol.,  2007, 75(1), 36-41.

[20]
Lahera, V.; Goicoechea, M.; Garcia de Vinuesa, S.; Miana, M.; Heras, N.; Cachofeiro, V.; Luño, J. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: Beneficial effects of statins. Curr. Med. Chem.,  2007, 14(2), 243-248.
 [http://dx.doi.org/10.2174/092986707779313381] [PMID: 17266583]

[21]
Nieuwdorp, M.; Stroes, E.S.G.; Kastelein, J.J.P. Normalization of metabolic syndrome using fenofibrate, metformin or their combination. Diabetes Obes. Metab.,  2007, 9(6), 869-878.
 [http://dx.doi.org/10.1111/j.1463-1326.2006.00668.x] [PMID: 17924869]

[22]
Parasuraman, S.; Raveendran, R.; Kesavan, R. Blood sample collection in small laboratory animals. J. Pharmacol. Pharmacother.,  2010, 1(2), 87-93.
 [http://dx.doi.org/10.4103/0976-500X.72350] [PMID: 21350616]

[23]
Esposito, K.; Nappo, F.; Marfella, R.; Giugliano, G.; Giugliano, F.; Ciotola, M.; Quagliaro, L.; Ceriello, A.; Giugliano, D. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation,  2002, 106(16), 2067-2072.
 [http://dx.doi.org/10.1161/01.CIR.0000034509.14906.AE] [PMID: 12379575]

[24]
Executive summary of the third report of the national cholesterol education program expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA,  2001, 285(19), 2486-2497.
 [http://dx.doi.org/10.1001/jama.285.19.2486] [PMID: 11368702]

[25]
Kannel, W.B.; Vasan, R.S.; Keyes, M.J.; Sullivan, L.M.; Robins, S.J. Usefulness of the triglyceride-high-density lipoprotein versus the cholesterol-high-density lipoprotein ratio for predicting insulin resistance and cardiometabolic risk (from the Framingham Offspring Cohort). Am. J. Cardiol.,  2008, 101(4), 497-501.
 [http://dx.doi.org/10.1016/j.amjcard.2007.09.109] [PMID: 18312765]

[26]
Baez-Duarte, B.G.; Zamora-Gínez, I.; González-Duarte, R.; Torres-Rasgado, E.; Ruiz-Vivanco, G.; Pérez-Fuentes, R.; Celis, T.M.R.G.O.D. Triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index as a reference criterion of risk for metabolic syndrome (MetS) and low insulin sensitivity in apparently healthy subjects. Gac. Med. Mex.,  2017, 153(2), 152-158.
 [PMID: 28474700]

[27]
Ratnoff, O.D.; Menzie, C. A new method for the determination of fibrinogen in small samples of plasma. J. Lab. Clin. Med.,  1951, 37(2), 316-320.
 [PMID: 14814359]

[28]
Moncada, S.; Palmer, R.M.J.; Higgs, A. The biological significance of nitric oxide formation from L -arginine. Biochem. Soc. Trans.,  1989, 17(4), 642-644.
 [http://dx.doi.org/10.1042/bst0170642] [PMID: 2670632]

[29]
Bergmeyer, HU Methods of Enzymatic Analysis, 3 Sub; , 1983. INCOMPLETE 

[30]
Woolliams, J.A.; Woolliams, G.; Anderson, P.H.; Mcmurray, C.H. Variation in the activities of glutathione peroxidase and superoxide dismutase and in the concentration of copper in the blood in various breed crosses of sheep. Res. Vet. Sci.,  1983, 34(3), 253-256.
 [http://dx.doi.org/10.1016/S0034-5288(18)32219-7] [PMID: 6878874]

[31]
Tarán, M.; Báez, M.; Scribano, M.P. Experimental model of oxidative stress markers in subclinical atherogenesis associated with metabolic syndrome. J. Cardiol. Cardiov. Dis,  2018, 4, 1021.

[32]
Reddy, P.; Lent-Schochet, D.; Ramakrishnan, N.; McLaughlin, M.; Jialal, I. Metabolic syndrome is an inflammatory disorder: A conspiracy between adipose tissue and phagocytes. Clin. Chim. Acta,  2019, 496, 35-44.
 [http://dx.doi.org/10.1016/j.cca.2019.06.019] [PMID: 31229566]

[33]
Kumar, S.; Singh, R.K.; Bhardwaj, T.R. Therapeutic role of nitric oxide as emerging molecule. Biomed. Pharmacother.,  2017, 85, 182-201.
 [http://dx.doi.org/10.1016/j.biopha.2016.11.125] [PMID: 27940398]

[34]
Spahis, S.; Borys, J.M.; Levy, E. Metabolic syndrome as a multifaceted risk factor for oxidative stress. Antioxid. Redox Signal.,  2017, 26(9), 445-461.
 [http://dx.doi.org/10.1089/ars.2016.6756] [PMID: 27302002]

[35]
Baez, M.D.C.; Tarán, M.; Moya, M.; Scribano Parada, M.D.L.P. Oxidative stress in metabolic syndrome: Experimental model of biomarkers. Modulation of Oxidative Stress in Heart Disease; Springer: Singapore, 2019, pp. 313-338.
 [http://dx.doi.org/10.1007/978-981-13-8946-7_12]

[36]
Monserrat-Mesquida, M.; Quetglas-Llabrés, M.; Capó, X.; Bouzas, C.; Mateos, D.; Pons, A.; Tur, J.A.; Sureda, A. Metabolic syndrome is associated with oxidative stress and proinflammatory state. Antioxidants,  2020, 9(3), 236.
 [http://dx.doi.org/10.3390/antiox9030236] [PMID: 32178436]

[37]
Albhaisi, S.; Sanyal, A.J. Applying non-invasive fibrosis measurements in NAFLD/NASH: progress to date. Pharmaceut. Med.,  2019, 33(6), 451-463.
 [http://dx.doi.org/10.1007/s40290-019-00305-z] [PMID: 31933238]

[38]
Zhao, X. From about the resveratrol the oxidative stress of high uric acid mediated the influence of nonalcoholic fatty liver disease in rats. Chin. Arch. Trad. Chin. Med.,  2016, 34(5), 1193-1196.

[39]
Ni, X.; Wang, H. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD). Am. J. Transl. Res.,  2016, 8(2), 1073-1081.
 [PMID: 27158393]

[40]
Chrysant, S.G. Authors reply: Statins and new onset of diabetes: Which one outweighs risk or benefit? Postgrad. Med.,  2018, 130(1), 147.
 [http://dx.doi.org/10.1080/00325481.2018.1396877] [PMID: 29065746]

[41]
Diamantis, E.; Kyriakos, G.; Quiles-Sanchez, L.V.; Farmaki, P.; Troupis, T. The anti-inflammatory effects of statins on coronary artery disease: an updated review of the literature. Curr. Cardiol. Rev.,  2017, 13(3), 209-216.
 [PMID: 28462692]

[42]
Tabrizi, R.; Tamtaji, O.R.; Mirhosseini, N.; Lankarani, K.B.; Akbari, M.; Dadgostar, E.; Borhani-Haghighi, A.; Peymani, P.; Ahmadizar, F.; Asemi, Z. The effects of statin use on inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res.,  2019, 141, 85-103.
 [http://dx.doi.org/10.1016/j.phrs.2018.12.010] [PMID: 30576798]

[43]
Mayyas, F.; Baydoun, D.; Ibdah, R.; Ibrahim, K. Atorvastatin reduces plasma inflammatory and oxidant biomarkers in patients with risk of atherosclerotic cardiovascular disease. J. Cardiovasc. Pharmacol. Ther.,  2018, 23(3), 216-225.
 [http://dx.doi.org/10.1177/1074248417753677] [PMID: 29343081]

[44]
Doumas, M.; Imprialos, K.; Dimakopoulou, A.; Stavropoulos, K.; Binas, A.; Athyros, V.G. The role of statins in the management of nonalcoholic fatty liver disease. Curr. Pharm. Des.,  2019, 24(38), 4587-4592.
 [http://dx.doi.org/10.2174/1381612825666190117114305] [PMID: 30652643]

[45]
Athyros, V.G.; Boutari, C.; Stavropoulos, K.; Anagnostis, P.; Imprialos, K.P.; Doumas, M.; Karagiannis, A. Statins: an under-appreciated asset for the prevention and the treatment of NAFLD or NASH and the related cardiovascular risk. Curr. Vasc. Pharmacol.,  2018, 16(3), 246-253.
 [http://dx.doi.org/10.2174/1570161115666170621082910] [PMID: 28676019]

[46]
Berg, E.H.; Wolters, A.A.B.; Dullaart, R.P.F.; Moshage, H.; Zurakowski, D.; de Meijer, V.E.; Blokzijl, H. Prescription of statins in suspected non‐alcoholic fatty liver disease and high cardiovascular risk, a population‐based study. Liver Int.,  2019, 39(7), 1343-1354.
 [http://dx.doi.org/10.1111/liv.14116] [PMID: 30968536]

[47]
Hassen, G.; Singh, A.; Belete, G.; Jain, N.; De la Hoz, I.; Camacho-Leon, G.P.; Dargie, N.K.; Carrera, K.G.; Alemu, T.; Jhaveri, S.; Solomon, N. Nonalcoholic fatty liver disease: An emerging modern-day risk factor for cardiovascular disease. Cureus,  2022, 14(5), e25495.
 [http://dx.doi.org/10.7759/cureus.25495] [PMID: 35783879]

[48]
Costache, I.I.; Garleanu, I.; Aursulesei, V.; Namat, R.A.; Ion, A.; Miftode, R.S.; Tesloianu, D.; Iliescu, D.; Petris, A.O.; Costache, A.D.; Popa, D.M.; Timpau, A.S. Atorvastatin in the treatment of dyslipidemic patients with very high cardiovascular risk and nonalcoholic fatty liver disease. Revista de Chimie,  2019, 70(6), 2159-2161.
 [http://dx.doi.org/10.37358/RC.19.6.7296]

[49]
Chalasani, N.; Younossi, Z.; Lavine, J.E.; Charlton, M.; Cusi, K.; Rinella, M.; Harrison, S.A.; Brunt, E.M.; Sanyal, A.J. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology,  2018, 67(1), 328-357.
 [http://dx.doi.org/10.1002/hep.29367] [PMID: 28714183]

[50]
Pose, E.; Trebicka, J.; Mookerjee, R.P.; Angeli, P.; Ginès, P. Statins: Old drugs as new therapy for liver diseases? J. Hepatol.,  2019, 70(1), 194-202.
 [http://dx.doi.org/10.1016/j.jhep.2018.07.019] [PMID: 30075229]

[51]
Kinaan, M.; Ding, H.; Triggle, C.R. Metformin: an old drug for the treatment of diabetes but a new drug for the protection of the endothelium. Med. Princ. Pract.,  2015, 24(5), 401-415.
 [http://dx.doi.org/10.1159/000381643] [PMID: 26021280]

[52]
Tokubuchi, I.; Tajiri, Y.; Iwata, S.; Hara, K.; Wada, N.; Hashinaga, T.; Nakayama, H.; Mifune, H.; Yamada, K. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS One,  2017, 12(2), e0171293.
 [http://dx.doi.org/10.1371/journal.pone.0171293] [PMID: 28158227]

[53]
Feng, W.H.; Bi, Y.; Li, P.; Yin, T.T.; Gao, C.X.; Shen, S.M.; Gao, L.J.; Yang, D.H.; Zhu, D.L. Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: A randomized trial. J. Diabetes Investig.,  2019, 10(2), 399-407.
 [http://dx.doi.org/10.1111/jdi.12888] [PMID: 29957886]

[54]
Dehkordi, A.H.; Abbaszadeh, A.; Mir, S.; Hasanvand, A. Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. J. Renal Inj. Prev.,  2018, 8(1), 54-61.
 [http://dx.doi.org/10.15171/jrip.2019.11]

[55]
Driver, C.; Bamitale, K.D.S.; Kazi, A.; Olla, M.; Nyane, N.A.; Owira, P.M.O. Cardioprotective effects of metformin. J. Cardiovasc. Pharmacol.,  2018, 72(2), 121-127.
 [http://dx.doi.org/10.1097/FJC.0000000000000599] [PMID: 29738369]

[56]

                                Jelić-Knezović, N.; 
                                Galijašević, S.; 
                                Lovrić, M.; 
                                Vasilj, M.; 
                                Selak, S.; 
                                Mikulić, I. Levels of nitric oxide metabolites and myeloperoxidase in subjects with type 2 diabetes mellitus on metformin therapy. Exp. Clin. Endocrinol. Diabet.,  2019, 6(1), 56-61.
 [http://dx.doi.org/10.1055/a-0577-7776] [PMID: 29529688]

[57]
Karise, I.; Ornellas, F.; Barbosa-da-Silva, S.; Matsuura, C.; del Sol, M.; Aguila, M.B.; Mandarim-de-Lacerda, C.A. Liver and Metformin: Lessons of a fructose diet in mice. Biochim. Open,  2017, 4, 19-30.
 [http://dx.doi.org/10.1016/j.biopen.2017.01.002] [PMID: 29450137]

[58]
Santos, A.G.; da Rocha, G.O.; & de Andrade, J.B. Occurrence of the potent mutagens 2- nitrobenzanthrone and 3-nitrobenzanthrone in fine airborne particles. Sci. Rep.,  2019, 9, 1.

[59]
Tseng, C.H. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int.,  2018, 38(11), 2018-2027.
 [http://dx.doi.org/10.1111/liv.13872] [PMID: 29956875]

[60]
Gamad, N.; Malik, S.; Suchal, K.; Vasisht, S.; Tomar, A.; Arava, S.; Arya, D.S.; Bhatia, J. Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: Pharmacological effects and molecular mechanisms. Biomed. Pharmacother.,  2018, 97, 1544-1553.
 [http://dx.doi.org/10.1016/j.biopha.2017.11.101] [PMID: 29793317]

[61]
Lonardo, A.; Lugari, S.; Ballestri, S.; Nascimbeni, F.; Baldelli, E.; Maurantonio, M. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol.,  2019, 56(4), 385-396.
 [http://dx.doi.org/10.1007/s00592-018-1266-0] [PMID: 30519965]

[62]
Marchisello, S.; Pino, A.D.; Scicali, R.; Urbano, F.; Piro, S.; Purrello, F.; Rabuazzo, A.M. Pathophysiological, molecular and therapeutic issues of nonalcoholic fatty liver disease: An overview. Int. J. Mol. Sci.,  2019, 20(8), 1948.
 [http://dx.doi.org/10.3390/ijms20081948] [PMID: 31010049]

[63]
Kothari, S.; Dhami-Shah, H.; Shah, S.R. Antidiabetic drugs and statins in nonalcoholic fatty liver disease. J. Clin. Exp. Hepatol.,  2019, 9(6), 723-730.
 [http://dx.doi.org/10.1016/j.jceh.2019.06.003] [PMID: 31889754]

[64]
Farah, S.; Nguyen, T.; Kelsberg, G.; Safranek, S. Metformin for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Am. Fam. Physician,  2019, 99(4), 262-263.
 [PMID: 30763050]

[65]
Hu, H.; Wang, J.; Li, X.; Shen, L.; Shi, D.; Meng, J. The effect of metformin on aminotransferase levels, metabolic parameters and body mass index in nonalcoholic fatty liver disease patients: A metaanalysis. Curr. Pharm. Des.,  2021, 27(29), 3235-3243.
 [http://dx.doi.org/10.2174/1381612827666210315144821] [PMID: 33719959]

[66]
Luo, F.; Guo, Y.; Li, X. Statins plus metformin: A promising combination for prevention and treatment of atherosclerosis. J. Adv. Therap. Medic. Innovation Sci.,  2016, 1, 56-57.
 [http://dx.doi.org/10.17987/jatamis.v1i0.332]

[67]
Preiss, D.; Lloyd, S.M.; Ford, I.; McMurray, J.J.; Holman, R.R.; Welsh, P.; Fisher, M.; Packard, C.J.; Sattar, N. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol.,  2014, 2(2), 116-124.
 [http://dx.doi.org/10.1016/S2213-8587(13)70152-9] [PMID: 24622715]

[68]
Luo, F.; Guo, Y.; Ruan, G.Y.; Long, J.K.; Zheng, X.L.; Xia, Q. Sci. Rep.,  2017, 7(1), 1-10.
 [http://dx.doi.org/10.1038/s41598-016-0028-x] [PMID: 28127051]

[69]
Zhang, J. Effect of atorvastatin combined with metformin on the lipid metabolism, hyperinsulinemia and oxidative stress in patients with nonalcoholic fatty liver disease. Hainan Yixueyuan Xuebao,  2017, 23(9), 60-63.

[70]
Sheka, A.C.; Adeyi, O.; Thompson, J.; Hameed, B.; Crawford, P.A.; Ikramuddin, S. Nonalcoholic steatohepatitis. JAMA,  2020, 323(12), 1175-1183.
 [http://dx.doi.org/10.1001/jama.2020.2298] [PMID: 32207804]

[71]
Hao, Z.; Liu, Y.; Liao, H.; Zheng, D.; Xiao, C.; Li, G. Atorvastatin plus metformin confer additive benefits on subjects with dyslipidemia and overweight/obese via reducing ROCK2 concentration. Exp. Clin. Endocrinol. Diabetes,  2016, 124(4), 246-250.
 [http://dx.doi.org/10.1055/s-0035-1569364] [PMID: 27123784]

[72]
Mundi, M.S.; Velapati, S.; Patel, J.; Kellogg, T.A.; Abu Dayyeh, B.K.; Hurt, R.T. Evolution of NAFLD and its management. Nutr. Clin. Pract.,  2020, 35(1), 72-84.
 [http://dx.doi.org/10.1002/ncp.10449] [PMID: 31840865]

[73]
Torres-Peña, J.D.; Martín-Piedra, L.; Fuentes-Jiménez, F. Statins in non-alcoholic steatohepatitis. Front. Cardiovasc. Med.,  2021, 8, 777131.
 [http://dx.doi.org/10.3389/fcvm.2021.777131] [PMID: 34901236]

[74]
Sookoian, S.; Pirola, C.J. Repurposing drugs to target nonalcoholic steatohepatitis. World J. Gastroenterol.,  2019, 25(15), 1783-1796.
 [http://dx.doi.org/10.3748/wjg.v25.i15.1783] [PMID: 31057294]

[75]
Sookoian, S.; Pirola, C.J. Review article: shared disease mechanisms between non-alcoholic fatty liver disease and metabolic syndrome - translating knowledge from systems biology to the bedside. Aliment. Pharmacol. Ther.,  2019, 49(5), 516-527.
 [http://dx.doi.org/10.1111/apt.15163] [PMID: 30714632]

[76]
Fiorucci, S.; Biagioli, M.; Distrutti, E. Future trends in the treatment of non-alcoholic steatohepatitis. Pharmacol. Res.,  2018, 134, 289-298.
 [http://dx.doi.org/10.1016/j.phrs.2018.07.014] [PMID: 30021122]

[77]
Polyzos, S.A.; Kang, E.S.; Boutari, C.; Rhee, E.J.; Mantzoros, C.S. Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metabolism,  2020, 111, 154203.
 [http://dx.doi.org/10.1016/j.metabol.2020.154203] [PMID: 32151660]

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DOI https://dx.doi.org/10.2174/1871523022666230223090714	Print ISSN 1871-5230
Publisher Name Bentham Science Publisher	Online ISSN 1875-614X

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Pharmacological Action of Atorvastatin and Metformin on Non-alcoholic Fatty Liver Disease on an Experimental Model of Metabolic Syndrome

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