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Medical Molecular Morphology

, Volume 52, Issue 4, pp 187–197 | Cite as

The therapeutic effects of resveratrol on hepatic steatosis in high-fat diet-induced obese mice by improving oxidative stress, inflammation and lipid-related gene transcriptional expression

  • Kang Cheng
  • Zhihua Song
  • Hao Zhang
  • Simian Li
  • Chao Wang
  • Lili Zhang
  • Tian WangEmail author
Original Paper

Abstract

So far, the majority of the previous animal studies have focused on the preventive effects of resveratrol (RSV) on non-alcoholic fatty liver disease (NAFLD) rather than the therapeutic effects. In this study, the therapeutic effects of RSV on hepatic oxidative stress (OS), inflammation, and lipid metabolism-related gene expression of obese mice induced by a high-fat diet (HFD) were investigated. Male C57BL/6 mice were fed a HFD for 8 weeks to induce obesity-related NAFLD model. And then, NAFLD mice were treated with daily RSV oral gavage at the dose of 100 mg/kg body weight for an additional 4 weeks. HFD-induced the elevation of serum total cholesterol, high-density lipoprotein cholesterol, glucose, insulin, aspartate aminotransferase and alanine aminotransferase levels, and homeostasis model assessment of insulin resistance, hepatic histology changes, the increases in hepatic triglyceride, malondialdehyde and tumor necrosis factor alpha concentrations, as well as the higher mRNA expression of hepatic toll-like receptor 4 and cluster of differentiation 36 in mice, were restored by RSV. The therapeutic effects of RSV against hepatic steatosis of HFD obese mice were attributed to the reduction of OS, inflammation and free fatty acid uptake.

Keywords

Resveratrol Hepatic steatosis Oxidative stress Inflammation Lipid metabolism Obesity 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant nos. 31772634, 31802094 and 31601948), the National Key Research and Development Program of China (Grant no. 2018YFD0501101), the Postdoctoral Research Foundation of China (Grant no. 2018M632320), the Natural Science Foundation of Jiangsu Province (Grant no. BK20180531), and the Open Project of Shanghai Key Laboratory of Veterinary Biotechnology (Grant no. klab201710).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interests.

References

  1. 1.
    Song HZ, Qiang C, Xu DD, Yang X, Zheng XD (2016) Purified betacyanins from Hylocereus undatus peel ameliorate obesity and insulin resistance in high-fat-diet-fed mice. J Agric Food Chem 64:236–244CrossRefGoogle Scholar
  2. 2.
    Kopelman PG (2000) Obesity as a medical problem. Nature 404:635–643CrossRefGoogle Scholar
  3. 3.
    Williamson RM, Price JF, Glancy S, Perry E, Nee LD, Hayes PC, Frier BM, Van Look LA, Johnston GI, Reynolds RM (2011) Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the edinburgh type 2 diabetes study. Diabetes Care 34:1139–1144CrossRefGoogle Scholar
  4. 4.
    Charytoniuk T, Drygalski K, Konstantynowicz-Nowicka K, Berk K, Chabowski A (2017) Alternative treatment methods attenuate the development of NAFLD: a review of resveratrol molecular mechanisms and clinical trials. Nutrition 34:108–117CrossRefGoogle Scholar
  5. 5.
    He HJ, Wang GY, Gao Y, Ling WH, Yu ZW, Jin TR (2012) Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World J Diabetes 3:94–104CrossRefGoogle Scholar
  6. 6.
    Lin ZH, Cai FF, Lin N, Ye JI, Zheng QQ, Ding GS (2014) Effects of glutamine on oxidative stress and nuclear factor-κB expression in the livers of rats with nonalcoholic fatty liver disease. Exp Ther Med 7:365–370CrossRefGoogle Scholar
  7. 7.
    Allen L, Ramalingam L, Menikdiwela K, Scoggin S, Shen CL, Tomison MD, Kaur G, Dufour JM, Chung E, Kalupahana NS, Moustaid-Moussa N (2017) Effects of delta-tocotrienol on obesity-related adipocyte hypertrophy, inflammation and hepatic steatosis in high-fat-fed mice. J Nutr Biochem 48:128–137CrossRefGoogle Scholar
  8. 8.
    Musso G, Gambino R, Cassader M (2009) Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 48:1–26CrossRefGoogle Scholar
  9. 9.
    Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–1846CrossRefGoogle Scholar
  10. 10.
    Wang S, Zhu MJ, Du M (2014) Prevention of obesity by dietary resveratrol: how strong is the evidence? Expert Rev Endocrinol Metab 10:561–564CrossRefGoogle Scholar
  11. 11.
    Tian Y, Ma J, Wang W, Zhang L, Xu J, Wang K, Li D (2016) Resveratrol supplement inhibited the NF-κB inflammation pathway through activating AMPKα-SIRT1 pathway in mice with fatty liver. Mol Cell Biochem 422:75–84CrossRefGoogle Scholar
  12. 12.
    Labbé A, Garand C, Cogger VC, Paquet ER, Desbiens M, Le CD, Lebel M (2011) Resveratrol improves insulin resistance hyperglycemia and hepatosteatosis but not hypertriglyceridemia, inflammation, and life span in a mouse model for Werner syndrome. J Gerontol A Biol Sci Med Sci 66:264–278CrossRefGoogle Scholar
  13. 13.
    Shakibaei M, Harikumar KB, Aggarwal BB (2009) Resveratrol addiction: to die or not to die. Mol Nutr Food Res 53:115–128CrossRefGoogle Scholar
  14. 14.
    Delmas D, Lançon A, Colin D, Jannin B, Latruffe N (2006) Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 7:423–442CrossRefGoogle Scholar
  15. 15.
    Heebøll S, Thomsen KL, Pedersen SB, Vilstrup H, George J, Grønbæk H (2014) Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease. World J Heoatol 6:188–198CrossRefGoogle Scholar
  16. 16.
    Andrade JM, Paraíso AF, de Oliveira MV, Martins AM, Neto JF, Guimarães AL, de Paula AM, Qureshi M, Santos SH (2014) Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition 30:915–919CrossRefGoogle Scholar
  17. 17.
    Cho SJ, Jung UJ, Chol MS (2012) Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice. Br J Nutr 108:2166–2175CrossRefGoogle Scholar
  18. 18.
    Zhu W, Chen S, Li Z, Zhao X, Li W, Sun Y, Zhang Z, Ling W, Feng X (2014) Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice. Nutr Metab 11:35CrossRefGoogle Scholar
  19. 19.
    Xu J, Zhang M, Zhang X, Yang H, Sun B, Wang Z, Zhou Y, Wang S, Liu X, Liu L (2018) Contribution of hepatic retinaldehyde dehydrogenase induction to impairment of glucose metabolism by high-fat diet feeding in C57BL/6J mice. Basic Clin Pharmacol Toxicol 123:539–548CrossRefGoogle Scholar
  20. 20.
    Li L, Hai J, Li Z, Zhang Y, Peng H, Li K, Weng X (2014) Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol 63:166–173CrossRefGoogle Scholar
  21. 21.
    Ji G, Wang Y, Deng Y, Li X, Jiang Z (2015) Resveratrol ameliorates hepatic steatosis and inflammation in methionine/choline-deficient diet-induced steatohepatitis through regulating autophagy. Lipids Health Dis 14:134CrossRefGoogle Scholar
  22. 22.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefGoogle Scholar
  23. 23.
    Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509PubMedPubMedCentralGoogle Scholar
  24. 24.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefGoogle Scholar
  25. 25.
    Cheng K, Song ZH, Zheng XC, Zhang H, Zhang JF, Zhang LL, Zhou YM, Wang T (2017) Effects of dietary vitamin E type on the growth performance and antioxidant capacity in cyclophosphamide immunosuppressed broilers. Poult Sci 96:1159–1166PubMedGoogle Scholar
  26. 26.
    Cheng K, Niu Y, Zheng XC, Zhang H, Chen YP, Zhang M, Huang XX, Zhang LL, Zhou YM, Wang T (2016) A comparison of natural (D-α-tocopherol) and synthetic (DL-α-tocopherol acetate) vitamin E supplementation on the growth performance, meat quality and oxidative status of broilers. Asian-Australas J Anim Sci 29:681–688CrossRefGoogle Scholar
  27. 27.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25:402–408CrossRefGoogle Scholar
  28. 28.
    Styskal JL, Remmen HV, Richardson A, Salmon AB (2012) Oxidative stress and diabetes: what can we learn about insulin resistance from antioxidant mutant mouse models? Free Radic Biol Med 52:46–58CrossRefGoogle Scholar
  29. 29.
    Madan K, Bhardwaj P, Thareja S, Gupta SD, Saraya A (2006) Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD). J Clin Gastroenterol 40:930–935CrossRefGoogle Scholar
  30. 30.
    Pan QR, Ren YL, Zhu JJ, Hu YJ, Zheng JS, Fan H, Xu Y, Wang G, Liu WX (2014) Resveratrol increases nephrin and podocin expression and alleviates renal damage in rats fed a high-fat diet. Nutrients 6:2619–2631CrossRefGoogle Scholar
  31. 31.
    Robb EL, Winkelmolen L, Visanji N, Brotchie J, Stuart JA (2008) Dietary resveratrol administration increases MnSOD expression and activity in mouse brain. Biochem Biophys Res Commun 372:254–259CrossRefGoogle Scholar
  32. 32.
    Truong VL, Jun M, Jeong WS (2018) Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors 44:36–49CrossRefGoogle Scholar
  33. 33.
    Jiang M, Li X, Yu X, Liu X, Xu X, He J, Gu H, Liu L (2017) Oral administration of resveratrol alleviates osteoarthritis pathology in C57BL/6J mice model induced by a high-fat diet. Mediators Inflamm 2017:7659023PubMedPubMedCentralGoogle Scholar
  34. 34.
    Yu S, Matsusue K, Kashireddy P, Cao WQ, Yeldandi V, Yeldandi AV, Rao MS, Gonzalez FJ, Reddy JK (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J Biol Chem 278:498–505CrossRefGoogle Scholar
  35. 35.
    Liu XJ, Wang BW, Zhang C, Xia MZ, Chen YH, Hu CQ, Wang H, Chen X, Xu DX (2015) Vitamin D deficiency attenuates high-fat diet-induced hyperinsulinemia and hepatic lipid accumulation in male mice. Endocrinology 156:2103–2113CrossRefGoogle Scholar
  36. 36.
    Koonen DP, Jacobs RL, Febbraio M, Young ME, Soltys CL, Ong H, Vance DE, Dyck JR (2007) Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 56:2863–2871CrossRefGoogle Scholar
  37. 37.
    Luiken JJ, Dyck DJ, Han XX, Tandon NN, Arumugam Y, Glatz JF, Bonen A (2002) Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane. Am J Physiol Endocrinol Metab 282:E491–E495CrossRefGoogle Scholar
  38. 38.
    Luiken JJ, Arumugam Y, Dyck DJ, Bell RC, Pelsers MM, Turcotte LP, Tandon NN, Glatz JF, Bonen A (2001) Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J Biol Chem 276:40567–40573CrossRefGoogle Scholar
  39. 39.
    Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, Laitinen S, Kolak M, Fisher RM, Hamsten A, Auvinen P, Yki-Jarvinen H (2008) Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 294:G1281–G1287CrossRefGoogle Scholar

Copyright information

© The Japanese Society for Clinical Molecular Morphology 2019

Authors and Affiliations

  • Kang Cheng
    • 1
  • Zhihua Song
    • 1
    • 2
  • Hao Zhang
    • 1
  • Simian Li
    • 1
  • Chao Wang
    • 1
  • Lili Zhang
    • 1
  • Tian Wang
    • 1
    Email author
  1. 1.College of Animal Science and TechnologyNanjing Agricultural UniversityNanjingChina
  2. 2.School of electrical and Electronic EngineeringAnhui Science and Technology UniversityBengbuChina

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