The therapeutic effects of berberine plus sitagliptin in a rat model of fatty liver disease

Document Type : Original Article

Authors

1 Department of Biology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

3 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Fatty liver disease (FLD) is a disorder related to accumulation of excess fat within the hepatocytes. In this study, the effects of Berberine, a natural compound, and Sitagliptin as a DPP-4 inhibitor, were observed in a rat model of FLD.
Materials and Methods: Forty male rats were divided into five groups (n=6) including the control group (normal food and water), high-fat group (high-fat diet (HF) for 6 weeks), Berberine group (HF with oral administration of Berberine at 150 mg/kg for 6 weeks), Sitagliptin group (HF with oral administration of Sitagliptin at 10 mg/kg for 6 weeks), and Berberine/ Sitagliptin group (HF diet within combination with oral administration of Berberine 75 mg/kg and Sitagliptin 5 mg/kg for 6 weeks). Animals were examined for weight gain, serum and hepatic biochemical parameters, tissue histology, expression of glucose transporter type 4 (GLUT4) mRNA, and protein expression of Adiponectin receptor2 (AdipoR2) and extracellular signal-regulated kinase (ERK) and phoERK.
Results: The results showed that ALT, AST, lipid profile, insulin, glucose, MDA, and TNF-α were significantly improved in high-fat rats treated with Berberine/ Sitagliptin compared with HF and Sitagliptin, and Berberine alone groups. SOD and adiponectin levels in Berberine/ Sitagliptin group were also significantly increased compared with the other groups. Immunoblot analysis showed that the expression of pho-ERK/ERK was significantly decreased and expression of AdipoR2 significantly increased in the Berberine/ Sitagliptin group compared with other groups.
Conclusion: Co-administration of Berberine and Sitagliptin is an effective therapeutic regimen for conditions associated with hyperlipidemia.

Keywords

References

1. Abd El-Kader SM, El-Den Ashmawy EM. Non-alcoholic fatty liver disease: The diagnosis and management. World J Hepatol 2015;7:846-58.
2. Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism 2019;92:82-97.
3. Brunt EM. A novel genetic marker of liver disease aetiology in hepatocellular carcinoma: Culling the metabolic syndrome. Gut 2013;62:808-809.
4. 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.
5. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-1321.
6.    Chao H-W, Chao S-W, Lin H, Ku H-C, Cheng C-F. Homeostasis of glucose and lipid in non-alcoholic fatty liver disease. Int J Mol Sci 2019;20:298.
7.Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism 2016;65:1096-1098.
8.    Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005;48:634-642.
9.    Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia 2009;13:9-19.
10. Sell H, Blüher M, Klöting N, Schlich R, Willems M, Ruppe F, et al. Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care 2013;36:4083-4090.
11. Nargis T, Chakrabarti P. Significance of circulatory DPP4 activity in metabolic diseases. IUBMB life 2018;70:112-119.
12. Parim B, Sathibabu Uddandrao VV, Saravanan G. Diabetic cardiomyopathy: molecular mechanisms, detrimental effects of conventional treatment, and beneficial effects of natural therapy. Heart Fail Rev 2019;24:279-299.
13. Itou M, Kawaguchi T, Taniguchi E, Sata M. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol 2013;19:2298-306.
14. Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol 2015;6:386.
15. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004;89:2078-2084.
16. Julienne KK, Elizabeth CO. Sitagliptin and vildagliptin: efficacy of therapy in type 2 diabetes. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2008;2:162-171.
17. Dave DJ. Saxagliptin: a dipeptidyl peptidase-4 inhibitor in the treatment of type 2 diabetes mellitus. J Pharmacol Pharmacother 2011;2:230-235.
18. Li Z, Geng Y-N, Jiang J-D, Kong W-J. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med 2014;2014:289-264.
19. Mahli A, Saugspier M, Koch A, Sommer J, Dietrich P, Lee S, et al. ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis. Gut 2018;67:746-756.
20. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006;116:1784-1792.
21. Heydari M, Cornide-Petronio ME, Jiménez-Castro MB, Peralta C. Data on adiponectin from 2010 to 2020: therapeutic target and prognostic factor for liver diseases? Int J Mol Sci 2020;21:5242.
22. Karim S, Adams DH, Lalor PF. Hepatic expression and cellular distribution of the glucose transporter family. World J Gastroenterol 2012;18:6771-6781.
23. Garabadu D, Krishnamurthy S. Metformin attenuates hepatic insulin resistance in type-2 diabetic rats through PI3K/Akt/GLUT-4 signalling independent to bicuculline-sensitive GABA(A) receptor stimulation. Pharm Biol 2017;55:722-8.
24. Jiao Y, Wang X, Jiang X, Kong F, Wang S, Yan C. Antidiabetic effects of Morus alba fruit polysaccharides on high-fat diet- and streptozotocin-induced type 2 diabetes in rats. J Ethnopharmacol 2017;199:119-127.
25. Zou Y, Li J, Lu C, Wang J, Ge J, Huang Y, et al. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sci 2006;79:1100-1107.
26. Vafaei R, Nassiri SM, Siavashi V. β3-Adrenergic Regulation of EPC Features Through Manipulation of the Bone Marrow MSC Niche. J Cell Biochem 2017;118:4753-4761.
27. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402-408.
28. Xu G, Huang K, Zhou J. Hepatic AMP kinase as a potential target for treating nonalcoholic fatty liver disease: evidence from Studies of natural products. Curr Med Chem 2018;25:889-907.
29. Pathak R, Kumar A, Palfrey HA, Forney LA, Stone KP, Raju NR, et al. The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet. Inflamm Res 2019;68:581-595.
30. Gomez-Peralta F, Abreu C, Gomez-Rodriguez S, Barranco RJ, Umpierrez GE. Safety and efficacy of DPP4 inhibitor and basal insulin in type 2 diabetes: an updated review and challenging clinical scenarios.  Diabetes Ther 2018;9:1775-1789.
31. Chen L, Teng H, Cao H. Chlorogenic acid and caffeic acid from Sonchus oleraceus Linn synergistically attenuate insulin resistance and modulate glucose uptake in HepG2 cells. Food Chem Toxicol 2019;127:182-187.
32. Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism 2009;58:109-119.
33. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006;40:17-29.
34. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006;7:85-96.
35. Xu B, Shen T, Chen L, Xia J, Zhang C, Wang H, et al. The effect of sitagliptin on lipid metabolism of fatty liver mice and related mechanisms. Med Sci Monit 2017;23:1363-1370.
36. Prakash S, Rai U, Kosuru R, Tiwari V, Singh S. Amelioration of diet-induced metabolic syndrome and fatty liver with sitagliptin via regulation of adipose tissue inflammation and hepatic Adiponectin/AMPK levels in mice. Biochimie 2020;168:198-209.
37. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762-769.
38. El-Zeftawy M, Ghareeb D, ElBealy ER, Saad R, Mahmoud S, Elguindy N, et al. Berberine chloride ameliorated PI3K/Akt-p/SIRT-1/PTEN signaling pathway in insulin resistance syndrome induced in rats. J Food Biochem 2019;43:13049.
39. Hussain M, Rafique MA, Iqbal J, Akhtar L. Effect of sitagliptin and glimepiride on C-reactive protein (CRP) in overweight Type-2 diabetic patients. Pak J Med Sci 2019;35:383-387.
40. Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab 2009;296: 955-964.
41. Ji LL, Stratman FW, Lardy HA. Antioxidant enzyme systems in rat liver and skeletal muscle. Influences of selenium deficiency, chronic training, and acute exercise. Arch Biochem Biophys 1988;263:150-160.
42. Li S, Hong M, Tan H-Y, Wang N, Feng Y. Insights into the role and interdependence of oxidative stress and inflammation in liver diseases. Oxid Med Cell Longev 2016;2016:4234061.
43. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015;62:47-64.
44. Pang B, Zhao L-H, Zhou Q, Zhao T-Y, Wang H, Gu C-J, et al. Application of berberine on treating type 2 diabetes mellitus. Int J Endocrinol 2015;2015:905749.
45. Day EA, Ford RJ, Steinberg GR. AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol Metab 2017;28:545-560.
46. Choi E, Kim W, Joo SK, Park S, Park JH, Kang YK, et al. Expression patterns of STAT3, ERK and estrogen-receptor α are associated with development and histologic severity of hepatic steatosis: a retrospective study. Diagn Pathol 2018;13:23.
47. Zeng Y, Li C, Guan M, Zheng Z, Li J, Xu W, et al. The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms. Cardiovasc Diabetol 2014;13:32.
48. Liang KW, Ting CT, Yin SC, Chen YT, Lin SJ, Liao JK, et al. Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury. Biochem Pharmacol 2006;71:806-817.
49. Wu YY, Zha Y, Liu J, Wang F, Xu J, Chen ZP, et al. Effect of berberine on the ratio of high-molecular weight adiponectin to total adiponectin and adiponectin receptors expressions in high-fat diet fed rats. Chin J Integr Med 2016.
50. Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, Takekawa S, et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem 2004;279:30817-30822.
51. Chen LN, Lyu J, Yang XF, Ji WJ, Yuan BX, Chen MX, et al. Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice. Int J Mol Med 2013;32:892-900.
52. Balakrishnan BB, Krishnasamy K, Choi KC. Moringa concanensis Nimmo ameliorates hyperglycemia in 3T3-L1 adipocytes by upregulating PPAR-γ, C/EBP-α via Akt signaling pathway and STZ-induced diabetic rats. Biomed Pharmacother 2018;103:719-728.
53. Giannocco G, Oliveira KC, Crajoinas RO, Venturini G, Salles TA, Fonseca-Alaniz MH, et al. Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats. Eur J Pharmacol 2013;698:74-86.
54. Hu H, Xu M, Qi R, Wang Y, Wang C, Liu J, et al. Sitagliptin downregulates retinol-binding protein 4 and upregulates glucose transporter type 4 expression in a type 2 diabetes mellitus rat model. Int J Clin Exp Med 2015;8:17902-17911.
55. Kim SH, Shin E-J, Kim E-D, Bayaraa T, Frost SC, Hyun C-K. Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes. Biol Pharm Bull 2007;30:2120-2125.
56. Zhang N, Liu X, Zhuang L, Liu X, Zhao H, Shan Y, et al. Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: Dual regulation of the PI3K/AKT and MAPK pathways. Regul Toxicol Pharmacol 2020;110:104544.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 4
April 2021
Pages 451-459

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