Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c
-
Nejat Kheiripour
, Jamshid Karimi, Iraj Khodadadi
, Heidar Tavilani , Mohammad Taghi Goodarzi and Mohammad Hashemnia
Abstract
Background:
In this study, we have investigated whether silymarin intake influences lipid and glycogen content in conjunction with sirtuin1 (SIRT1) and sterol regulatory element-binding protein 1c (SREBP-1c) expressions in liver of type 2 diabetic rat.
Methods:
Thirty-six male Wistar rats were randomly divided into six groups: control groups (C) and diabetic groups (D); the control groups received 60 or 120 mg/kg silymarin (C+S60 or C+S120), and the diabetic groups received 60 or 120 mg/kg silymarin (D+S60 or D+S120) daily for 8 weeks. Serum biochemical parameters, as well as glycogen, lipid and oxidative stress biomarkers, in the liver tissue were measured by spectrophotometric methods. Additionally, SIRT1 and SREBP-1c messenger RNA (mRNA) expressions were evaluated by quantitative polymerase chain reaction.
Results:
Diabetes caused a significantly increased fasting blood sugar, homeostasis model assessment for insulin resistance, liver total cholesterol and triglyceride (TG) content, which were attenuated after the administration of silymarin. Dietary silymarin caused the improvement of lipid content in the liver of diabetic rats. Moreover, silymarin administration promoted SIRT1, suppressed SREBP-1c mRNA expression, reduced liver nitric oxide and protein carbonyl content, and increased liver glycogen, catalase and glutathione peroxidase activity. Furthermore, histopathological changes were improved in the treated groups.
Conclusions:
Silymarin administration considerably restored hepatic changes induced by streptozotocin and nicotinamide. The upregulation of SIRT1 mRNA expression by silymarin may be associated with decreased lipid, increased glycogen content and downregulation of the SREBP-1c gene in the liver.
Acknowledgments
This study was financially supported by the Hamadan University of Medical Sciences (Funder Id: 10.13039/501100004697, No. 9505052617). The results presented in this article were part of N. Kheiripour’s Ph.D. thesis.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.
Research funding: Hamadan University of Medical Sciences (No. 9505052617).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009;32:S62–7.10.2337/dc09-S062Search in Google Scholar PubMed PubMed Central
2. Farid O, Hebi M, Ajebli M, Hidani AE, Eddouks M. Antidiabetic effect of Ruta montana L. in streptozotocin-induced diabetic rats. J Basic Clin Physiol Pharmacol 2017;28:275–82.10.1515/jbcpp-2016-0030Search in Google Scholar PubMed
3. Krssak M, Roden M. The role of lipid accumulation in liver and muscle for insulin resistance and type 2 diabetes mellitus in humans. Rev Endocr Metab Disord 2004;5:127–34.10.1023/B:REMD.0000021434.98627.dcSearch in Google Scholar PubMed
4. Jung UJ, Lee M-K, Jeong K-S, Choi M-S. The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J Nutr 2004;134:2499–503.10.1093/jn/134.10.2499Search in Google Scholar PubMed
5. Defour A, Dessalle K, Perez AC, Poyot T, Castells J, Gallot YS, et al. Sirtuin 1 regulates SREBP-1c expression in a LXR-dependent manner in skeletal muscle. PLoS One 2012;7:e43490.10.1371/journal.pone.0043490Search in Google Scholar PubMed PubMed Central
6. Ponugoti B, Kim D-H, Xiao Z, Smith Z, Miao J, Zang M, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010;285:33959–70.10.1074/jbc.M110.122978Search in Google Scholar PubMed PubMed Central
7. Pettinelli P, Del Pozo T, Araya J, Rodrigo R, Araya AV, Smok G, et al. Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim Biophys Acta 2009;1792:1080–6.10.1016/j.bbadis.2009.08.015Search in Google Scholar PubMed
8. Zanganeh N, Siahpoushi E, Kheiripour N, Kazemi S, Goodarzi MT, Alikhani MY. Brucellosis causes alteration in trace elements and oxidative stress factors. Biol Trace Elem Res 2017:1–5. [Epub ahead of print]. doi: 10.1007/s12011-017-1102-3.10.1007/s12011-017-1102-3Search in Google Scholar PubMed
9. Khazaei M, Karimi J, Sheikh N, Goodarzi MT, Saidijam M, Khodadadi I, et al. Effects of resveratrol on receptor for advanced glycation end products (RAGE) expression and oxidative stress in the liver of rats with type 2 diabetes. Phytother Res 2016;30:66–71.10.1002/ptr.5501Search in Google Scholar PubMed
10. Lee J, Homma T, Kurahashi T, Kang ES, Fujii J. Oxidative stress triggers lipid droplet accumulation in primary cultured hepatocytes by activating fatty acid synthesis. Biochem Biophys Res Commun 2015;464:229–35.10.1016/j.bbrc.2015.06.121Search in Google Scholar PubMed
11. Sekiya M, Hiraishi A, Touyama M, Sakamoto K. Oxidative stress induced lipid accumulation via SREBP1c activation in HepG2 cells. Biochem Biophys Res Commun 2008;375:602–7.10.1016/j.bbrc.2008.08.068Search in Google Scholar PubMed
12. Mohammadian A, Moradkhani S, Ataei S, Shayesteh TH, Sedaghat M, Kheiripour N, et al. Antioxidative and hepatoprotective effects of hydroalcoholic extract of Artemisia absinthium L. in rat. J HerbMed Pharmacol 2016;5:29–32.Search in Google Scholar
13. Feher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol 2012;13:210–7.10.2174/138920112798868818Search in Google Scholar PubMed
14. Pradhan S, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res 2006;124:491–504.Search in Google Scholar PubMed
15. Sheela N, Jose MA, Sathyamurthy D, Kumar BN. Effect of silymarin on streptozotocin-nicotinamide-induced type 2 diabetic nephropathy in rats. Iran J Kidney Dis 2013;7:117–23.Search in Google Scholar PubMed
16. Farimani AR, Saidijam M, Goodarzi MT, Azari RY, Asadi S, Zarei S, et al. Effect of resveratrol supplementation on the SNARE proteins expression in adipose tissue of stroptozotocin-nicotinamide induced type 2 diabetic rats. Iran J Med Sci 2015;40:248–55.Search in Google Scholar PubMed
17. Bahabadi M, Mohammadalipour A, Karimi J, Sheikh N, Solghi G, Goudarzi F, et al. Hepatoprotective effect of parthenolide in rat model of nonalcoholic fatty liver disease. Immunopharmacol Immunotoxicol 2017;39:233–42.10.1080/08923973.2017.1327965Search in Google Scholar PubMed
18. Koroliuk MA, Ivanova LI, Maiorova IG, Tokarev VE. A method of determining catalase activity. Lab Delo 1988;1:16–9.Search in Google Scholar
19. Dubinina EE, Burmistrov SO, Khodov DA, Porotov IG. Oxidative modification of human serum proteins. A method of determining it. Vopr Med Khim 1995;41:24–6.Search in Google Scholar PubMed
20. Granger DL, Taintor RR, Boockvar KS, Hibbs JB Jr. Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol 1996;268:142–51.10.1016/S0076-6879(96)68016-1Search in Google Scholar PubMed
21. Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882–8.Search in Google Scholar PubMed
22. Francini F, Castro MC, Schinella G, García ME, Maiztegui B, Raschia MA, et al. Changes induced by a fructose-rich diet on hepatic metabolism and the antioxidant system. Life Sci 2010;86:965–71.10.1016/j.lfs.2010.05.005Search in Google Scholar PubMed
23. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957;226:497–509.10.1016/S0021-9258(18)64849-5Search in Google Scholar PubMed
24. Kim MK, Hyun SH, Choung SY. Effect of herbal extract mixtures on serum and liver lipid metabolism in chronic ethanol-administered rats. J Health Sci 2006;52:344–51.10.1248/jhs.52.344Search in Google Scholar
25. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 2001;25:402–8.10.1006/meth.2001.1262Search in Google Scholar PubMed
26. Slaoui M, Fiette L. Histopathology procedures: from tissue sampling to histopathological evaluation. Methods in molecular biology. Methods Mol Biol 2011;691:69–82.10.1007/978-1-60761-849-2_4Search in Google Scholar PubMed
27. Ghadermazi R, Khoshjou F, Hossini Zijoud SM, Behrooj H, Kheiripour N, Ganji M, et al. Hepatoprotective effect of tempol on oxidative toxic stress in STZ-induced diabetic rats. Toxin Rev 2017;37:82–6.10.1080/15569543.2017.1313277Search in Google Scholar
28. Vargas-Mendoza N, Madrigal-Santillán E, Morales-González Á, Esquivel-Soto J, Esquivel-Chirino C, García-Luna y González-Rubio M, et al. Hepatoprotective effect of silymarin. World J Hepatol 2014;6:144–9.10.4254/wjh.v6.i3.144Search in Google Scholar PubMed PubMed Central
29. El-Far M, Negm A, Wahdan M. Promising biopharmaceutical use of silymarin and silibinin as antidiabetic natural agents in streptozotocin-induced diabetic rats: first comparative assessment. World J Pharm Pharm Sci 2014;4:7–28.Search in Google Scholar
30. Soto C, Mena R, Luna J, Cerbon M, Larrieta E, Vital P, et al. Silymarin induces recovery of pancreatic function after alloxan damage in rats. Life Sci 2004;75:2167–80.10.1016/j.lfs.2004.04.019Search in Google Scholar PubMed
31. Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism 2014;63:1469–79.10.1016/j.metabol.2014.08.010Search in Google Scholar PubMed
32. Parhofer KG. Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia. Diabetes Metab J 2015;39:353–62.10.4093/dmj.2015.39.5.353Search in Google Scholar PubMed PubMed Central
33. Sajedianfard J, Behroozi Z, Nazifi S. The effects of a hydroalcoholic extract of silymarin on serum lipids profiles in streptozotocin induced diabetic rats. Comp Clin Pathol 2014;23:779–84.10.1007/s00580-013-1688-6Search in Google Scholar
34. Vats V, Yadav S, Grover J. Ethanolic extract of Ocimum sanctum leaves partially attenuates streptozotocin-induced alterations in glycogen content and carbohydrate metabolism in rats. J Ethnopharmacol 2004;90:155–60.10.1016/j.jep.2003.09.034Search in Google Scholar PubMed
35. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008;118: 829–38.10.1172/JCI34275Search in Google Scholar PubMed PubMed Central
36. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA 2008;105:9793–8.10.1073/pnas.0802917105Search in Google Scholar PubMed PubMed Central
37. Di Naso FC, Simões Dias A, Porawski M, Marroni NAP. Exogenous superoxide dismutase: action on liver oxidative stress in animals with streptozotocin-induced diabetes. Exp Diabetes Res 2011;2011:1–6.10.1155/2011/754132Search in Google Scholar PubMed PubMed Central
38. Oyenihi OR, Brooks NL, Oguntibeju OO. Effects of kolaviron on hepatic oxidative stress in streptozotocin induced diabetes. BMC Complement Altern Med 2015;15:236–43.10.1186/s12906-015-0760-ySearch in Google Scholar PubMed PubMed Central
39. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 2012;56:952–64.10.1016/j.jhep.2011.08.025Search in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- Calcium sensitization mechanisms in detrusor smooth muscles
- Opinion Paper
- The case for a distinctive philosophy of physiology and pathophysiology
- Behavior and Neuroprotection
- Effects of dizocilpine-induced glutamatergic blockade in the nucleus accumbens septi on the plus maze test
- Reproduction
- [6]-Gingerol modulates spermatotoxicity associated with ulcerative colitis and benzo[a]pyrene exposure in BALB/c mice
- Cardiovascular Function
- Blood troponin levels in acute cardiac events depends on space weather activity components (a correlative study)
- Effects of Trypanosoma brucei brucei infection and diminazene aceturate administration on the blood pressure, heart rate, and temperature of Wistar albino rats
- Oxidative Stress
- Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis
- Metabolism
- Losartan improves renal function and pathology in obese ZSF-1 rats
- Phytotherapy
- Evaluation of morning glory (Jacquemontia tamnifolia (L.) Griseb) leaves for antioxidant, antinociceptive, anticoagulant and cytotoxic activities
- Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c
Articles in the same Issue
- Frontmatter
- Review
- Calcium sensitization mechanisms in detrusor smooth muscles
- Opinion Paper
- The case for a distinctive philosophy of physiology and pathophysiology
- Behavior and Neuroprotection
- Effects of dizocilpine-induced glutamatergic blockade in the nucleus accumbens septi on the plus maze test
- Reproduction
- [6]-Gingerol modulates spermatotoxicity associated with ulcerative colitis and benzo[a]pyrene exposure in BALB/c mice
- Cardiovascular Function
- Blood troponin levels in acute cardiac events depends on space weather activity components (a correlative study)
- Effects of Trypanosoma brucei brucei infection and diminazene aceturate administration on the blood pressure, heart rate, and temperature of Wistar albino rats
- Oxidative Stress
- Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis
- Metabolism
- Losartan improves renal function and pathology in obese ZSF-1 rats
- Phytotherapy
- Evaluation of morning glory (Jacquemontia tamnifolia (L.) Griseb) leaves for antioxidant, antinociceptive, anticoagulant and cytotoxic activities
- Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c