Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical nutrition

The efficacy of flaxseed and hesperidin on non-alcoholic fatty liver disease: an open-labeled randomized controlled trial

European Journal of Clinical Nutrition volume 75, pages 99–111 (2021)Cite this article

Subjects

Abstract

Background/Objectives

Non-alcoholic fatty liver disease (NAFLD) is growing in prevalence globally and no definitive evidence for any approved pharmacological approaches for patients with NAFLD has been found yet. This study was aimed to assess the clinical effects of flaxseed and hesperidin in patients with NAFLD.

Subjects/methods

In this randomized, controlled, clinical trial, one hundred eligible patients with NAFLD were enrolled and randomly assigned to four dietary intervention groups including lifestyle modification program (control), lifestyle modification program with 30 g whole flaxseed powder, lifestyle modification program with 1 g hesperidin supplementation, and lifestyle modification program with combination of 30 g flaxseed and 1 g hesperidin (flax-hes) for 12 weeks. The changes in anthropometric parameters, metabolic profiles of glucose and lipids, inflammatory biomarkers and hepatic steatosis and fibrosis were evaluated.

Results

After the 12-week dietary interventions, significant reductions in body mass index, glucose hemostasis parameters and hepatic steatosis were observed in all groups. Repeated measures analysis of variance revealed a significant effect for time relative to almost all paraclinical parameters. Post hoc analysis with Bonferroni correction revealed that the three intervention groups experienced significant decreases in plasma levels of alanine aminotransferase, indices of insulin resistance and insulin sensitivity, fasting glucose and fatty liver index compared to control (p < 0.008).

Conclusions

In conclusion, our study confirmed that hesperidin and flaxseed supplementation improved glucose and lipid metabolism, while reduced inflammation and hepatic steatosis (controlled attenuation parameter) in NAFLD patients. The synergistic effects of their combination were observed on plasma glucose concentration and HOMA-IR.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The study consort flowchart.
Fig. 2: Comparison of steatosis percent reduction (%) across all groups at different degrees of body weight change (<5%, 5–10% and ≥10% body weight change).
Fig. 3: Box plot of the fasting glucose; insulin and HOMA-IR at baseline (T0) and at the end of trial (T12), among four groups, with a significant improvement in all groups over the intervention (p < 0.05).

References

  1. Liver EAFTSOT, Diabetes EAftSo. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Obes Facts. 2016;9:65–90.

    Google Scholar 

  2. Vernon G, Baranova A, Younossi Z. Systematic review: the epidemiology and natural history of non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–85.

    CAS  PubMed  Google Scholar 

  3. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138–53.

    PubMed  Google Scholar 

  4. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184–96.

    CAS  PubMed  Google Scholar 

  5. Watanabe M, Tozzi R, Risi R, Tuccinardi D, Mariani S, Basciani S, et al. Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: a comprehensive review of the literature. Obes Rev. 2020;21:e13024.

  6. Laursen TL, Hagemann CA, Wei C, Kazankov K, Thomsen KL, Knop FK, et al. Bariatric surgery in patients with non-alcoholic fatty liver disease-from pathophysiology to clinical effects. World J Hepatol. 2019;11:138.

    PubMed  PubMed Central  Google Scholar 

  7. Bao L, Yin J, Gao W, Wang Q, Yao W, Gao X. A long‐acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non‐alcoholic steatohepatitis partly through an FGF21‐adiponectin‐IL17A pathway. Br J Pharmacol. 2018;175:3379–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sattar N, Forrest E, Preiss D. Non-alcoholic fatty liver disease. BMJ. 2014;349:24–8.

    Google Scholar 

  9. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012;56:255–66.

    PubMed  Google Scholar 

  10. Mazzella N, Ricciardi LM, Mazzotti A, Marchesini G. The role of medications for the management of patients with NAFLD. Clin Liver Dis. 2014;18:73–89.

    PubMed  Google Scholar 

  11. Asrih M, Jornayvaz FR. Diets and nonalcoholic fatty liver disease: the good and the bad. Clin Nutr. 2014;33:186–90.

    PubMed  Google Scholar 

  12. Dudekula A, Rachakonda V, Shaik B, Behari J. Weight loss in nonalcoholic Fatty liver disease patients in an ambulatory care setting is largely unsuccessful but correlates with frequency of clinic visits. PLoS ONE. 2014;9:e111808.

    PubMed  PubMed Central  Google Scholar 

  13. Greenway F. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes. 2015;39:1188.

    CAS  Google Scholar 

  14. Pugh CJ, Sprung V, Jones H, Richardson P, Shojaee-Moradie F, Umpleby AM, et al. Exercise-induced improvements in liver fat and endothelial function are not sustained 12 months following cessation of exercise supervision in nonalcoholic fatty liver disease. Int J Obes. 2016;40:1927.

    CAS  Google Scholar 

  15. Mokhtari Z, Poustchi H, Eslamparast T, Hekmatdoost A. Egg consumption and risk of non-alcoholic fatty liver disease. World J Hepatol. 2017;9:503–9.

    PubMed  PubMed Central  Google Scholar 

  16. Noori M, Jafari B, Hekmatdoost A. Pomegranate juice prevents development of non-alcoholic fatty liver disease in rats by attenuating oxidative stress and inflammation. J Sci Food Agric. 2017;97:2327–32.

    CAS  PubMed  Google Scholar 

  17. Rahimlou M, Yari Z, Hekmatdoost A, Alavian SM, Keshavarz SA. Ginger supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Hepat Mon. 2016;16:e34897.

    PubMed  PubMed Central  Google Scholar 

  18. Emamat H, Foroughi F, Eini-Zinab H, Taghizadeh M, Rismanchi M, Hekmatdoost A. The effects of onion consumption on treatment of metabolic, histologic, and inflammatory features of nonalcoholic fatty liver disease. J Diabetes Metab Disord. 2015;15:25.

    PubMed  Google Scholar 

  19. Yari Z, Rahimlou M, Eslamparast T, Ebrahimi-Daryani N, Poustchi H, Hekmatdoost A. Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study. Int J Food Sci Nutr. 2016;67:461–9.

    CAS  PubMed  Google Scholar 

  20. Morris DH. Flax: a health and nutrition primer. Flax Council of Canada; Winnipeg, MB, Canada, 2007.

  21. Daun JK, Barthet VJ, Chornick TL, Duguid S. Structure, composition, and variety development of flaxseed. Flaxseed in human nutrition: AOCS Publishing; Champaign, Illinois, 2003. p. 6–45.

  22. Hassanali Z, Ametaj B, Field C, Proctor S, Vine D. Dietary supplementation of n‐3 PUFA reduces weight gain and improves postprandial lipaemia and the associated inflammatory response in the obese JCR: LA‐cp rat. Diabetes Obes Metab. 2010;12:139–47.

    CAS  PubMed  Google Scholar 

  23. Tai CC, Ding ST. N-3 polyunsaturated fatty acids regulate lipid metabolism through several inflammation mediators: mechanisms and implications for obesity prevention. J Nutr Biochem. 2010;21:357–63.

    CAS  PubMed  Google Scholar 

  24. Yari Z, Rahimlou M, Poustchi H, Hekmatdoost A. Flaxseed supplementation in metabolic syndrome management: a pilot randomized, open‐labeled, controlled study. Phytother Res. 2016;30:1339–44.

    CAS  PubMed  Google Scholar 

  25. Rhee Y, Brunt A. Flaxseed supplementation improved insulin resistance in obese glucose intolerant people: a randomized crossover design. Nutr J. 2011;10:44.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Edel AL, Rodriguez-Leyva D, Maddaford TG, Caligiuri SP, Austria JA, Weighell W, et al. Dietary flaxseed independently lowers circulating cholesterol and lowers it beyond the effects of cholesterol-lowering medications alone in patients with peripheral artery disease–4. J Nutr. 2015;145:749–57.

    CAS  PubMed  Google Scholar 

  27. Mohammadi‐Sartang M, Mazloom Z, Raeisi‐Dehkordi H, Barati‐Boldaji R, Bellissimo N, Totosy, et al. The effect of flaxseed supplementation on body weight and body composition: a systematic review and meta‐analysis of 45 randomized placebo‐controlled trials. Obes Rev. 2017;18:1096–107.

    PubMed  Google Scholar 

  28. Yari Z, Rahimlou M, Hekmatdoost A. Flaxseed supplementation improves anthropometric measurements, metabolic, and inflammatory biomarkers in overweight and obese adults. Int J Vitamin Nutr Res. 2019;1–8.

  29. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79:727–47.

    CAS  PubMed  Google Scholar 

  30. Rizza S, Muniyappa R, Iantorno M, Kim J-A, Chen H, Pullikotil P, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011;96:E782–E92.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Parhiz H, Roohbakhsh A, Soltani F, Rezaee R, Iranshahi M. Antioxidant and anti‐inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res. 2015;29:323–31.

    CAS  PubMed  Google Scholar 

  32. De Ledinghen V, Vergniol J. Transient elastography (fibroscan). Gastroenterol Clin Biol. 2008;32:58–67.

    PubMed  Google Scholar 

  33. Initiative NOE, Heart N, Lung, Institute B, Obesity NAAftSo, Identification EPot, et al. The practical guide: identification, evaluation, and treatment of overweight and obesity in adults: The Institute; Bethesda, Maryland, 2000.

  34. Kelishadi R, Rabiei K, Khosravi A, Famouri F, Sadeghi M, Rouhafza H, et al. Assessment of physical activity of adolescents in Isfahan. J Shahrekord Univ Med Sci. 2001;3:55–66.

  35. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.

    CAS  PubMed  Google Scholar 

  36. Simental-Mendía LE, Rodríguez-Morán M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord. 2008;6:299–304.

    PubMed  Google Scholar 

  37. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–10.

    CAS  PubMed  Google Scholar 

  38. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.

    PubMed  PubMed Central  Google Scholar 

  39. Ruffillo G, Fassio E, Alvarez E, Landeira G, Longo C, Domínguez N, et al. Comparison of NAFLD fibrosis score and BARD score in predicting fibrosis in nonalcoholic fatty liver disease. J Hepatol. 2011;54:160–3.

    PubMed  Google Scholar 

  40. Torkan M, Entezari MH, Siavash M. Effect of flaxseed on blood lipid level in hyperlipidemic patients. Rev Recent Clin Trials. 2015;10:61–7.

    CAS  PubMed  Google Scholar 

  41. Patade A, Devareddy L, Lucas EA, Korlagunta K, Daggy BP, Arjmandi BH. Flaxseed reduces total and LDL cholesterol concentrations in Native American postmenopausal women. J Women’s Health. 2002;17:355–66. 2008

    Google Scholar 

  42. Xu J, Yang W, Deng Q, Huang Q, Huang F. Flaxseed oil and α-lipoic acid combination reduces atherosclerosis risk factors in rats fed a high-fat diet. Lipids Health Dis. 2012;11:148.

    PubMed  PubMed Central  Google Scholar 

  43. Di Y, Jones J, Mansell K, Whiting S, Fowler S, Thorpe L, et al. Influence of flaxseed lignan supplementation to older adults on biochemical and functional outcome measures of inflammation. J Am Coll Nutr. 2017;36:646–53.

    CAS  PubMed  Google Scholar 

  44. Felmlee MA, Woo G, Simko E, Krol ES, Muir AD, Alcorn J. Effects of the flaxseed lignans secoisolariciresinol diglucoside and its aglycone on serum and hepatic lipids in hyperlipidaemic rats. Br J Nutr. 2009;102:361–9.

    CAS  PubMed  Google Scholar 

  45. Salden BN, Troost FJ, de Groot E, Stevens YR, Garcés-Rimón M, Possemiers S, et al. Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals. Am J Clin Nutr. 2016;104:1523–33.

    CAS  PubMed  Google Scholar 

  46. Mohammadi M, Ramezani-Jolfaie N, Lorzadeh E, Khoshbakht Y, Salehi-Abargouei A. Hesperidin, a major flavonoid in orange juice, might not affect lipid profile and blood pressure: a systematic review and meta-analysis of randomized controlled clinical trials. Phytother Res. 2019;33:534–45.

  47. Jung UJ, Lee M-K, Park YB, Kang MA, Choi M-S. Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int J Biochem cell Biol. 2006;38:1134–45.

    CAS  PubMed  Google Scholar 

  48. Lawrenz J, Herndon B, Kamal A, Mehrer A, Dim DC, Baidoo C, et al. Dietary flaxseed oil protects against bleomycin-induced pulmonary fibrosis in rats. Pulmonary medicine. 2012;2012:457031.

  49. Xu J, Gao H, Song L, Yang W, Chen C, Deng Q, et al. Flaxseed oil and alpha-lipoic acid combination ameliorates hepatic oxidative stress and lipid accumulation in comparison to lard. Lipids Health Dis. 2013;12:58.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Dentin R, Benhamed F, Pégorier J-P, Foufelle F, Viollet B, Vaulont S, et al. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. The. J Clin Investig. 2005;115:2843–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Marx N, Duez H, Fruchart J-C, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res. 2004;94:1168–78.

    CAS  PubMed  Google Scholar 

  52. Jump DB. N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr Opin Lipidol. 2008;19:242.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hutchins AM, Brown BD, Cunnane SC, Domitrovich SG, Adams ER, Bobowiec CE. Daily flaxseed consumption improves glycemic control in obese men and women with pre-diabetes: a randomized study. Nutr Res. 2013;33:367–75.

    CAS  PubMed  Google Scholar 

  54. Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, et al. Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Am J Clin Nutr. 2010;91:940–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Hallund J, Tetens I, Bügel S, Tholstrup T, Bruun JM. The effect of a lignan complex isolated from flaxseed on inflammation markers in healthy postmenopausal women. Nutr Metab Cardiovas Dis. 2008;18:497–502.

    CAS  Google Scholar 

  56. Nasri K, Hantoushzadeh S, Aghadavod E, Taghizadeh M, Asemi Z. The effects of omega-3 fatty acids supplementation on gene expression involved in the insulin and lipid signaling pathway in patients with polycystic ovary syndrome. Horm Metab Res. 2017;49:446–51.

    CAS  PubMed  Google Scholar 

  57. Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-α expression by preventing NF-κB activation. J Am Coll Nutr. 2004;23:71–8.

    CAS  PubMed  Google Scholar 

  58. Malekzadeh R, Poustchi H. Fibroscan for assessing liver fibrosis: an acceptable alternative for liver biopsy: Fibroscan: an acceptable alternative for liver biopsy. Hepat Mon. 2011;11:157.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge all patients who accepted to participate in this study.

Author information

Authors and Affiliations

  1. Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Yari & Azita Hekmatdoost

  2. Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Makan Cheraghpour

  3. Middle East Liver Diseases (MELD) Center, Tehran, Iran

    Seyed Moayed Alavian

  4. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mehdi Hedayati

  5. Department of Community Nutrition, National Nutrition and Food Technology Research Institute; and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hassan Eini-Zinab

Authors
  1. Zahra Yari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makan Cheraghpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seyed Moayed Alavian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mehdi Hedayati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hassan Eini-Zinab
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Azita Hekmatdoost
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZY was responsible for conceptualization and designing the study, recruiting and following patients, writing the manuscript. MC was responsible for conceptualization and designing the study, providing supplements and commercial kits, reviewing the manuscript. SMA was responsible forassessing liver steatosis using a transient elastography (FibroScan). MH was responsible for biochemical evaluations in samples collected, using the relative kits, according to the manufacturer’s instructions. HEZ was responsible for statistical analyzing. AH was responsible for conceptualization and designing the study, project administration, writing, review and editing the manuscript.

Corresponding authors

Correspondence to Makan Cheraghpour or Azita Hekmatdoost.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yari, Z., Cheraghpour, M., Alavian, S.M. et al. The efficacy of flaxseed and hesperidin on non-alcoholic fatty liver disease: an open-labeled randomized controlled trial. Eur J Clin Nutr 75, 99–111 (2021). https://doi.org/10.1038/s41430-020-0679-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-020-0679-3

This article is cited by

Search

Advanced search

Quick links