Skip to main content
SpringerLink
Log in

Therapeutic Effects of Resveratrol on Nonalcoholic Fatty Liver Disease Through Inflammatory, Oxidative Stress, Metabolic, and Epigenetic Modifications

  • Protocol
  • First Online:
Physical Exercise and Natural and Synthetic Products in Health and Disease

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2343))

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing around the world, in association with the progressive elevation in overweight and obesity. The accumulation of lipids in NAFLD patients contributes to the development of insulin resistance, inflammation and oxidative stress in hepatocytes, and alteration of blood lipids and glycaemia. There are currently no effective pharmacological therapies for NAFLD, although lifestyle and dietary modifications targeting weight reduction are among the prevailing alternative approaches. For this reason, new approaches should be investigated. The natural polyphenol resveratrol represents a potential new treatment for management of NAFLD due to anti-inflammatory and antioxidant properties. Although preclinical trials have demonstrated promising results of resveratrol against NALFD, the lack of conclusive results creates the need for more trials with larger numbers of patients, longer time courses, and standardized protocols.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 34(3):274–285

    Article  CAS  PubMed  Google Scholar 

  2. Adams LA, Anstee QM, Tilg H, Targher G (2017) Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 66(6):1138–1153

    Article  PubMed  Google Scholar 

  3. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K et al (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55(6):2005–2023

    Article  PubMed  Google Scholar 

  4. Theodotou M, Fokianos K, Moniatis D, Kadlenic R, Chrysikou A, Aristotelous A et al (2019) Effect of resveratrol on non-alcoholic fatty liver disease. Exp Ther Med 18(1):559–565

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu FB, Hu ED, Xu LM, Chen L, Wu JL, Li H et al (2018) The relationship between obesity and the severity of non-alcoholic fatty liver disease: systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 12(5):491–502

    Article  CAS  PubMed  Google Scholar 

  6. Polyzos SA, Kountouras J, Mantzoros CS (2017) Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol 42(2):92–108

    PubMed  Google Scholar 

  7. Perumpail BJ, Khan MA, Yoo ER, Cholankeril G, Kim D, Ahmed A (2017) Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol 23(47):8263–8276

    Article  PubMed  PubMed Central  Google Scholar 

  8. Schuppan D, Gorrell MD, Klein T, Mark M, Afdhal NH (2010) The challenge of developing novel pharmacological therapies for non-alcoholic steatohepatitis. Liver Int 30(6):795–808

    Article  CAS  PubMed  Google Scholar 

  9. Gu Y, Lambert JD (2013) Modulation of metabolic syndrome-related inflammation by cocoa. Mol Nutr Food Res 57(6):948–961

    Article  CAS  PubMed  Google Scholar 

  10. Rodriguez-Mateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L et al (2014) Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update. Arch Toxicol 88(10):1803–1853

    Article  CAS  PubMed  Google Scholar 

  11. Springer M, Moco S (2019) Resveratrol and its human metabolites-effects on metabolic health and obesity. Nutrients 11(1):143. https://doi.org/10.3390/nu11010143

    Article  CAS  PubMed Central  Google Scholar 

  12. Burns J, Yokota T, Ashihara H, Lean ME, Crozier A (2002) Plant foods and herbal sources of resveratrol. J Agric Food Chem 50(11):3337–3340

    Article  CAS  PubMed  Google Scholar 

  13. Smoliga JM, Vang O, Baur JA (2012) Challenges of translating basic research into therapeutics: resveratrol as an example. J Gerontol A Biol Sci Med Sci 67(2):158–167

    Article  PubMed  CAS  Google Scholar 

  14. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127(6):1109–1122

    Article  CAS  PubMed  Google Scholar 

  15. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ et al (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15(5):675–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346(16):1221–1231

    Article  CAS  PubMed  Google Scholar 

  17. Clark JM (2006) The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40:S5–S10

    PubMed  Google Scholar 

  18. Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62(1):S47–S64

    Article  PubMed  Google Scholar 

  19. Saviano MC, Brunetti F, Rubino A, Franzese A, Vajro P, Argenziano A et al (1997) Liver involvement in obese children (ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population). Dig Dis Sci 42(7):1428–1432

    Article  PubMed  Google Scholar 

  20. Bellentani S, Scaglioni F, Marino M, Bedogni G (2010) Epidemiology of non-alcoholic fatty liver disease. Dig Dis 28(1):155–161

    Article  PubMed  CAS  Google Scholar 

  21. Berlanga A, Guiu-Jurado E, Porras JA, Auguet T (2014) Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol 7:221–239

    PubMed  PubMed Central  Google Scholar 

  22. Serviddio G, Bellanti F, Vendemiale G (2013) Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radic Biol Med 65:952–968

    Article  CAS  PubMed  Google Scholar 

  23. Gupte AA, Lyon CJ, Hsueh WA (2013) Nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2), a key regulator of the antioxidant response to protect against atherosclerosis and nonalcoholic steatohepatitis. Curr Diab Rep 13(3):362–371

    Article  CAS  PubMed  Google Scholar 

  24. Gutteridge JM, Halliwell B (1992) Comments on review of free radicals in biology and medicine, by Barry Halliwell and John MC Gutteridge. Free Radic Biol Med 12(1):93–95

    Article  CAS  PubMed  Google Scholar 

  25. Ashraf NU, Sheikh TA (2015) Endoplasmic reticulum stress and oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Free Radic Res 49(12):1405–1418

    Article  CAS  PubMed  Google Scholar 

  26. Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52(5):1836–1846

    Article  CAS  PubMed  Google Scholar 

  27. Schwabe RF, Uchinami H, Qian T, Bennett BL, Lemasters JJ, Brenner DA (2004) Differential requirement for c-Jun NH2-terminal kinase in TNFα- and Fas-mediated apoptosis in hepatocytes. FASEB J 18(6):720–722

    Article  CAS  PubMed  Google Scholar 

  28. Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18(49):6853–6866

    Article  CAS  PubMed  Google Scholar 

  29. Diehl AM (2004) Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis 8(3):619–638

    Article  PubMed  Google Scholar 

  30. Ricapa JG, Grueso RL, González GO, de la Torre MI, Abdelazid K, El Alami M et al (2013) Resveratrol: distribution, properties and perspectives. Rev Esp Geriatr Gerontol 48(2):79–88

    Article  Google Scholar 

  31. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79(5):727–747

    Article  CAS  PubMed  Google Scholar 

  32. Salvador I, Massarioli AP, Silva AP, Malaguetta H, Melo PS, Alencar SM (2019) Can we conserve trans-resveratrol content and antioxidant activity during industrial production of chocolate? J Sci Food Agric 99(1):83–89

    Article  CAS  PubMed  Google Scholar 

  33. Lancon A, Delma D, Osman H, Thénot JP, Jannin B, Latruffe N (2004) Human hepatic cell uptake of resveratrol: involvement of both passive diffusion and carrier-mediated process. Biochem Biophys Res Commun 316(4):1132–1137

    Article  CAS  PubMed  Google Scholar 

  34. Wang P, Sang S (2018) Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors 44(1):16–25

    Article  CAS  PubMed  Google Scholar 

  35. Wu T, Grootaert C, Voorspoels S, Jacobs G, Pitart J, Kamiloglu S et al (2017) Aronia (Aroniamelanocarpa) phenolics bioavailability in a combined in vitro digestion/Caco-2 cell model is structure and colon region dependent. J Funct Foods 38:128–139

    Article  CAS  Google Scholar 

  36. Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Vescovi PP et al (2005) Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res 49(5):495–504

    Article  CAS  PubMed  Google Scholar 

  37. Wenzel E, Somoza V (2005) Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res 49(5):472–481

    Article  CAS  PubMed  Google Scholar 

  38. Amri A, Chaumeil JC, Sfar S, Charrueau C (2012) Administration of resveratrol: what formulation solutions to bioavailability limitations? J Control Release 158(2):182–193

    Article  CAS  PubMed  Google Scholar 

  39. Huang XT, Li X, Xie ML, Huang Z, Huang YX, Wu GX et al (2019) Resveratrol: review on its discovery, anti-leukemia effects, pharmacokinetics. Chem Biol Interact 306:29–38

    Article  CAS  PubMed  Google Scholar 

  40. Chow HH, Garland LL, Hsu CH, Vining DR, Chew WM, Miller JA et al (2010) Resveratrol modulates drugandcarcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res (Phila) 3(9):1168–1175

    Article  CAS  Google Scholar 

  41. Izdebska M, Piątkowska-Chmiel I, Korolczuk A, Herbet M, Gawrońska-Grzywacz M, Gieroba R et al (2017) The beneficial effects of resveratrol on steatosis and mitochondrial oxidative stress in HepG2 cells. Can J Physiol Pharmacol 95(12):1442–1453

    Article  CAS  PubMed  Google Scholar 

  42. Izdebska M, Herbet M, Gawrońska-Grzywacz M, Piątkowska-Chmiel I, Korga A, Sysa M et al (2018) Resveratrol limits lipogenesis and enhance mitochondrial activity in HepG2 cells. J Pharm Pharm Sci 21(1):504–515

    Article  PubMed  Google Scholar 

  43. Rafiei H, Omidian K, Bandy B (2017) Comparison of dietary polyphenols for protection against molecular mechanisms underlying nonalcoholic fatty liver disease in a cell model of steatosis. Mol Nutr Food Res 61(9). https://doi.org/10.1002/mnfr.201600781

  44. Li YH, Choi DH, Lee EH, Seo SR, Lee S, Cho EH (2016) Sirtuin 3 (SIRT3) regulates α-smooth muscle actin (α-SMA) production through the succinate dehydrogenase-G protein-coupled receptor 91 (GPR91) pathway in hepatic stellate cells. J Biol Chem 291(19):10277–10292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang Y, Lang H, Chen K, Zhang Y, Gao Y, Ran L et al (2020) Resveratrol protects against nonalcoholic fatty liver disease by improving lipid metabolism and redox homeostasis via the PPARα pathway. Appl Physiol Nutr Metab 45(3):227–239

    Article  CAS  PubMed  Google Scholar 

  46. Bujanda L, Hijona E, Larzabal M, Beraza M, Aldazabal P, García-Urkia N et al (2008) Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol 8:40. https://doi.org/10.1186/1471-230X-8-40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Poulsen MM, Larsen JØ, Hamilton-Dutoit S, Clasen BF, Jessen N, Paulsen SK et al (2012) Resveratrol up-regulates hepatic uncoupling protein 2 and prevents development of nonalcoholic fatty liver disease in rats fed a high-fat diet. Nutr Res 32(9):701–708

    Article  CAS  PubMed  Google Scholar 

  48. Andrade JMO, Paraíso AF, de Oliveira MVM, Martins AME, Neto JF, Guimarães ALS et al (2014) Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition 30(7-8):915–919

    Article  CAS  PubMed  Google Scholar 

  49. Ali MH, Messiha BA, Abdel-Latif HA (2016) Protective effect of ursodeoxycholic acid, resveratrol, and N acetylcysteine on nonalcoholic fatty liver disease in rats. Pharm Biol 54(7):1198–1208

    CAS  PubMed  Google Scholar 

  50. Khaleel EF, Abdel-Aleem GA, Mostafa DG (2018) Resveratrol improves high-fat diet induced fatty liver and insulin resistance by concomitantly inhibiting proteolytic cleavage of sterol regulatory element binding proteins, free fatty acid oxidation, and intestinal triglyceride absorption. Can J Physiol Pharmacol 96(2):145–157

    Article  CAS  PubMed  Google Scholar 

  51. Xu K, Liu S, Zhao X, Zhang X, Fu X, Zhou Y et al (2019) Treating hyperuricemia related non-alcoholic fatty liver disease in rats with resveratrol. Biomed Pharmacother 110:844–849

    Article  CAS  PubMed  Google Scholar 

  52. Kessoku T, Imajo K, Honda Y, Kato T, Ogawa Y, Tomeno W et al (2016) Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep 6:22251. https://doi.org/10.1038/srep22251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chachay VS, Macdonald GA, Martin JH, Whitehead JP, O’Moore-Sullivan TM, Lee P et al (2014) Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Nutr Res 12(12):2092–2103

    CAS  Google Scholar 

  54. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A (2014) Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res 34(10):837–843

    Article  CAS  PubMed  Google Scholar 

  55. Heebøll S, Kreuzfeldt M, Hamilton-Dutoit S, Poulsen MK, Stødkilde-Jørgensen H, Møller HJ et al (2016) Placebo-controlled, randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease. Scand J Gastroenterol 51(4):456–464

    Article  PubMed  CAS  Google Scholar 

  56. Asghari S, Rafraf M, Farzin L, Asghari-Jafarabadi M, Ghavami SM, Somi MH (2018) Effects of pharmacologic dose of resveratrol supplementation on oxidative/antioxidative status biomarkers in nonalcoholic fatty liver disease patients: a randomized, double-blind, placebo-controlled trial. Adv Pharm Bull 8(2):307–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kantartzis K, Fritsche L, Bombrich M, Machann J, Schick F, Staiger H et al (2018) Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: a randomized, double-blind, placebo-controlled clinical trial. Diabetes Obes Metab 20(7):1793–1797

    Article  CAS  PubMed  Google Scholar 

  58. Poulsen MK, Nellemann B, Bibby BM, Stødkilde-Jørgensen H, Pedersen SB, Grønbæk H et al (2018) No effect of resveratrol on VLDL-TG kinetics and insulin sensitivity in obese men with nonalcoholic fatty liver disease. Diabetes Obes Metab 20(10):2504–2509

    Article  CAS  PubMed  Google Scholar 

  59. Chen S, Zhao X, Ran L, Wan J, Wang X, Qin Y et al (2015) Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig Liver Dis 47(3):226–232

    Article  CAS  PubMed  Google Scholar 

  60. Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C et al (2008) Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 27(5):412–421

    Article  CAS  PubMed  Google Scholar 

  61. Chu CJ, Lu RH, Wang SS, Chang FY, Wu SL, Lu CL et al (2007) Risk factors associated with non-alcoholic fatty liver disease in Chinese patients and the role of tumor necrosis factor-alpha. Hepato-Gastroenterology 54(79):2099–2102

    CAS  PubMed  Google Scholar 

  62. 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(1):134. https://doi.org/10.1186/s12944-015-0139-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu Z, Jiang C, Zhang J, Liu B, Du Q (2016) Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities. J Diabetes 8(3):324–335

    Article  CAS  PubMed  Google Scholar 

  64. Suenaga F, Hatsushika K, Takano S, Ando T, Ohnuma Y, Ogawa H et al (2008) A possible link between resveratrol and TGF-β: resveratrol induction of TGF-β expression and signaling. FEBS Lett 582(5):586–590

    Article  CAS  PubMed  Google Scholar 

  65. Tilg H, Moschen AR, Szabo G (2016) Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 64(3):955–965

    Article  CAS  PubMed  Google Scholar 

  66. Yang SJ, Lim Y (2014) Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism 63(5):693–701

    Article  CAS  PubMed  Google Scholar 

  67. Manna SK, Mukhopadhyay A, Aggarwal BB (2000) Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164(12):6509–6519

    Article  CAS  PubMed  Google Scholar 

  68. Li L, Hai J, Li Z, Zhang Y, Peng H, Li K et al (2014) Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol 63:166–173

    Article  CAS  PubMed  Google Scholar 

  69. Ma C, Wang Y, Dong L, Li M, Cai W (2015) Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways. Acta Biochim Biophys Sin Shanghai 47(3):207–213

    Article  CAS  PubMed  Google Scholar 

  70. Shi SY, Martin RG, Duncan RE, Choi D, Lu SY, Schroer SA et al (2012) Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance. J Biol Chem 287(13):10277–10288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sumida Y, Niki E, Naito Y, Yoshikawa T (2013) Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res 47(11):869–880

    Article  CAS  PubMed  Google Scholar 

  72. Gómez-Zorita S, Fernández-Quintela A, Macarulla MT, Aguirre L, Hijona E, Bujanda L et al (2012) Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. Br J Nutr 107(2):202–210

    Article  PubMed  CAS  Google Scholar 

  73. Tang Y, Xu J, Qu W, Peng X, Xin P, Yang X et al (2012) Resveratrol reduces vascular cell senescence through attenuation of oxidative stress by SIRT1/NADPH oxidase-dependent mechanisms. J Nutr Biochem 23(11):1410–1416

    Article  CAS  PubMed  Google Scholar 

  74. Subauste AR, Burant CF (2007) Role of FoxO1 in FFA-induced oxidative stress in adipocytes. Am J Physiol Endocrinol Metab 293(1):E159–E164

    Article  CAS  PubMed  Google Scholar 

  75. Zhu W, Chen S, Li Z, Zhao X, Li W, Sun Y et al (2014) Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice. Nutr Metab (Lond) 11(1):35. https://doi.org/10.1186/1743-7075-11-35

    Article  CAS  Google Scholar 

  76. Hori YS, Kuno A, Hosoda R, Horio Y (2013) Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS One 8(9):e73875. https://doi.org/10.1371/journal.pone.0073875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Spanier G, Xu H, Xia N, Tobias S, Deng S, Wojnowski L et al (2009) Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4). J Physiol Pharmacol 60(Suppl 4):111–116

    PubMed  Google Scholar 

  78. Chen F, Qian LH, Deng B, Liu ZM, Zhao Y, Le YY (2013) Resveratrol protects vascular endothelial cells from high glucose–induced apoptosis through inhibition of NADPH oxidase activation–driven oxidative stress. CNS Neurosci Ther 19(9):675–681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Choi YJ, Suh HR, Yoon Y, Lee KJ, Kim DG, Kim S et al (2014) Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase. Arch Pharm Res 37(9):1169–1176

    Article  CAS  PubMed  Google Scholar 

  80. Ajmo JM, Liang X, Rogers CQ, Pennock B, You M (2008) Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 295(4):G833–G842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jeon SM, Lee SA, Choi MS (2014) Antiobesity and vasoprotective effects of resveratrol in apoE-deficient mice. J Med Food 17(3):310–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Xin P, Han H, Gao D, Cui W, Yang X, Ying C et al (2013) Alleviative effects of resveratrol on nonalcoholic fatty liver disease are associated with up regulation of hepatic low density lipoprotein receptor and scavenger receptor class B type I gene expressions in rats. Food Chem Toxicol 52:12–18

    Article  CAS  PubMed  Google Scholar 

  83. Momchilova A, Petkova D, Staneva G, Markovska T, Pankov R, Skrobanska R et al (2014) Resveratrol alters the lipid composition, metabolism and peroxide level in senescent rat hepatocytes. Chem Biol Interact 207:74–80

    Article  CAS  PubMed  Google Scholar 

  84. Nagle CA, Klett EL, Coleman RA (2009) Hepatic triacylglycerol accumulation and insulin resistance. J Lipid Res 50(Supplement):S74–S79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F et al (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 298(4):E751–E760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13(4):225–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H et al (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148(3):421–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458(7241):1056–1060

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kang W, Hong HJ, Guan J, Kim DG, Yang EJ, Koh G et al (2012) Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents. Metabolism 61(3):424–433

    Article  CAS  PubMed  Google Scholar 

  90. Burgess TA, Robich MP, Chu LM, Bianchi C, Sellke FW (2011) Improving glucose metabolism with resveratrol in a swine model of metabolic syndrome through alteration of signaling pathways in the liver and skeletal muscle. Arch Surg 146(5):556–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Vetterli L, Brun T, Giovannoni L, Bosco D, Maechler P (2011) Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E β-cells and human islets through a SIRT1-dependent mechanism. J Biol Chem 286(8):6049–6060

    Article  CAS  PubMed  Google Scholar 

  92. Zhang J, Chen L, Zheng J, Zeng T, Li H, Xiao H et al (2012) The protective effect of resveratrol on islet insulin secretion and morphology in mice on a high-fat diet. Diabetes Res Clin Pract 97(3):474–482

    Article  CAS  PubMed  Google Scholar 

  93. Shang J, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H (2008) Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase. Acta Pharmacol Sin 29(6):698–706

    Article  CAS  PubMed  Google Scholar 

  94. Ma J, Zhou Q, Li H (2017) Gut microbiota and nonalcoholic fatty liver disease: insights on mechanisms and therapy. Nutrients 9(10):1124. https://doi.org/10.3390/nu9101124

    Article  CAS  PubMed Central  Google Scholar 

  95. Abu-Shanab A, Quigley EM (2010) The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7(12):691–701

    Article  PubMed  Google Scholar 

  96. Cani PD, Delzenne NM (2007) Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care 10(6):729–734

    Article  PubMed  Google Scholar 

  97. Campbell CL, Yu R, Li F, Zhou Q, Chen D, Qi C et al (2019) Modulation of fat metabolism and gut microbiota by resveratrol on high-fat diet-induced obese mice. Diabetes Metab Syndr Obes 12:97–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang P, Li D, Ke W, Liang D, Hu X, Chen F (2020) Resveratrol-induced gut microbiota reduces obesity in high-fat diet-fed mice. Int J Obes 44(1):213–225

    Article  CAS  Google Scholar 

  99. Etxeberria U, Arias N, Boqué N, Macarulla MT, Portillo MP, Martínez JA et al (2015) Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. J Nutr Biochem 26(6):651–660

    Article  CAS  PubMed  Google Scholar 

  100. Slocum SL, Skoko JJ, Wakabayashi N, Aja S, Yamamoto M, Kensler TW et al (2016) Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet. Arch Biochem Biophys 591:57–65

    Article  CAS  PubMed  Google Scholar 

  101. Chambel SS, Santos-Gonçalves A, Duarte TL (2015) The dual role of Nrf2 in nonalcoholic fatty liver disease: regulation of antioxidant defenses and hepatic lipid metabolism. Biomed Res Int 2015:597134. https://doi.org/10.1155/2015/597134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Uruno A, Yagishita Y, Yamamoto M (2015) The Keap1–Nrf2 system and diabetes mellitus. Arch Biochem Biophys 566:76–84

    Article  CAS  PubMed  Google Scholar 

  103. Palsamy P, Subramanian S (2011) Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2–Keap1 signaling. Biochim Biophys Acta 1812(7):719–731

    Article  CAS  PubMed  Google Scholar 

  104. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K et al (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299(1):H18–H24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rubiolo JA, Mithieux G, Vega FV (2008) Resveratrol protects primary rat hepatocytes against oxidative stress damage:: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. Eur J Pharmacol 591(1-3):66–72

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran

    Mina Karimi & Mohammadreza Vafa

  2. Department of Nutrition, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Behnaz Abiri

  3. Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil

    Paul C. Guest

  4. Charlesworth House, Debden, Essex, UK

    Paul C. Guest

Authors
  1. Mina Karimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Behnaz Abiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul C. Guest
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammadreza Vafa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammadreza Vafa .

Editor information

Editors and Affiliations

  1. Charlesworth House, Debden, Essex, UK

    Paul C. Guest

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Karimi, M., Abiri, B., Guest, P.C., Vafa, M. (2022). Therapeutic Effects of Resveratrol on Nonalcoholic Fatty Liver Disease Through Inflammatory, Oxidative Stress, Metabolic, and Epigenetic Modifications. In: Guest, P.C. (eds) Physical Exercise and Natural and Synthetic Products in Health and Disease. Methods in Molecular Biology, vol 2343. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1558-4_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1558-4_2

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1557-7

  • Online ISBN: 978-1-0716-1558-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation