Erythrocyte membrane n-3 polyunsaturated fatty acids are inversely associated with the presence and progression of nonalcoholic fatty liver disease in Chinese adults: a prospective study

Abstract

Purpose

Previous studies have shown that high-dose supplementation with n-3 polyunsaturated fatty acids (PUFAs) may benefit patients with nonalcoholic fatty liver disease (NAFLD), but the association of n-3 PUFAs with NAFLD among individuals with normal diets is only speculative. We investigated the cross-sectional and prospective associations between n-3 PUFAs and NAFLD in Chinese adults.

Methods

This community-based prospective study included 3049 men and women (40–75 years) in Guangzhou, China, whose participants completed an NAFLD ultrasound evaluation and erythrocyte PUFA tests. A total of 2660 participants underwent the second NAFLD evaluation approximately 3 years later. α-Linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocytes were measured by gas chromatography.

Results

After adjusting for potential confounders, we observed inverse associations between DHA, DHA + EPA, total n-3 PUFAs and the presence of NAFLD in the cross-sectional analysis. The adjusted odds ratios (95% confidence interval) of NAFLD for the highest (vs. lowest) tertile were 0.74 (0.61, 0.90) for DHA, 0.82 (0.67, 1.00) for EPA, 0.73 (0.60, 0.88) for DHA + EPA and 0.74 (0.61, 0.91) for total n-3 PUFAs  (all P values≤0.05). Over the average 3.12 years of follow-up, higher levels of DHA was associated with an improvement of NAFLD. The hazard ratio of improved NAFLD for the highest tertile was 1.18 (95% CI 1.09, 1.33) for DHA. Pathway analyses showed that favorable associations may be mediated by improvements in inflammatory markers (e.g., interleukin 1 beta and tumor necrosis factor alpha-like).

Conclusions

Erythrocyte membrane n-3 PUFAs are inversely associated with the presence and progression of NAFLD in Chinese adults.

Trial registrations

ClinicalTrials.gov NCT03179657.

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

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64(1):73–84. https://doi.org/10.1002/hep.28431

    Article  Google Scholar 

  2. 2.

    Sun Q, Ma J, Campos H, Hankinson SE, Hu FB (2007) Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women. Am J Clin Nutr 86(1):74–81. https://doi.org/10.1093/ajcn/86.1.74

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Serra-Majem L, Nissensohn M, Overby NC, Fekete K (2012) Dietary methods and biomarkers of omega 3 fatty acids: a systematic review. Br J Nutr 107(Suppl 2):S64–76. https://doi.org/10.1017/s000711451200147x

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Patterson AC, Chalil A, Aristizabal Henao JJ, Streit IT, Stark KD (2015) Omega-3 polyunsaturated fatty acid blood biomarkers increase linearly in men and women after tightly controlled intakes of 0.25, 0.5, and 1 g/d of EPA + DHA. Nutr Res 35(12):1040–1051. https://doi.org/10.1016/j.nutres.2015.09.016

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Calder PC (2012) Mechanisms of action of (n-3) fatty acids. J Nutr 142(3):592S–599S. https://doi.org/10.3945/jn.111.155259

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Calder PC (2010) Omega-3 fatty acids and inflammatory processes. Nutrients 2(3):355–374. https://doi.org/10.3390/nu2030355

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kong W, Yen JH, Vassiliou E, Adhikary S, Toscano MG, Ganea D (2010) Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family. Lipids Health Dis 9:12. https://doi.org/10.1186/1476-511X-9-12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Guo XF, Yang B, Tang J, Li D (2018) Fatty acid and non-alcoholic fatty liver disease: Meta-analyses of case-control and randomized controlled trials. Clin Nutr 37(1):113–122. https://doi.org/10.1016/j.clnu.2017.01.003

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Oya J, Nakagami T, Sasaki S, Jimba S, Murakami K, Kasahara T, Wasada T, Sekiguchi H, Hasegawa M, Endo Y, Iwamoto Y (2010) Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women. Eur J Clin Nutr 64(10):1179–1185. https://doi.org/10.1038/ejcn.2010.139

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J (2012) Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 56(4):944–951. https://doi.org/10.1016/j.jhep.2011.08.018

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Spadaro L, Magliocco O, Spampinato D, Piro S, Oliveri C, Alagona C, Papa G, Rabuazzo AM, Purrello F (2008) Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 40(3):194–199. https://doi.org/10.1016/j.dld.2007.10.003

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, Moyses HE, Calder PC, Byrne CD (2014) Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology 60(4):1211–1221. https://doi.org/10.1002/hep.27289

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Kris-Etherton PM, Innis S, Ammerican Dietetic A, Dietitians of C (2007) Position of the American Dietetic Association and Dietitians of Canada: dietary fatty acids. J Am Diet Assoc 107(9):1599–1611. https://doi.org/10.1016/j.jada.2007.07.024

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Cao WT, He J, Chen GD, Wang C, Qiu R, Chen YM (2017) The association between urinary sodium to potassium ratio and bone density in middle-aged Chinese adults. Osteoporos Int 28(3):1077–1086. https://doi.org/10.1007/s00198-016-3835-9

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Zhang CX, Ho SC (2009) Validity and reproducibility of a food frequency Questionnaire among Chinese women in Guangdong province. Asia Pac J Clin Nutr 18(2):240–250

    CAS  PubMed  Google Scholar 

  16. 16.

    Zeng MD, Fan JG, Lu LG, Li YM, Chen CW, Wang BY, Mao YM, Chinese National Consensus Workshop on Nonalcoholic Fatty Liver D (2008) Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases. J Digest Dis 9(2):108–112. https://doi.org/10.1111/j.1751-2980.2008.00331.x

    Article  Google Scholar 

  17. 17.

    Petit JM, Guiu B, Duvillard L, Jooste V, Brindisi MC, Athias A, Bouillet B, Habchi M, Cottet V, Gambert P, Hillon P, Cercueil JP, Verges B (2012) Increased erythrocytes n-3 and n-6 polyunsaturated fatty acids is significantly associated with a lower prevalence of steatosis in patients with type 2 diabetes. Clin Nutr 31(4):520–525. https://doi.org/10.1016/j.clnu.2011.12.007

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Lu W, Li S, Li J, Wang J, Zhang R, Zhou Y, Yin Q, Zheng Y, Wang F, Xia Y, Chen K, Liu T, Lu J, Zhou Y, Guo C (2016) Effects of Omega-3 fatty acid in nonalcoholic fatty liver disease: a meta-analysis. Gastroenterol Res Pract 2016:1459790. https://doi.org/10.1155/2016/1459790

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    He XX, Wu XL, Chen RP, Chen C, Liu XG, Wu BJ, Huang ZM (2016) Effectiveness of Omega-3 polyunsaturated fatty acids in non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. PLoS One 11(10):e0162368. https://doi.org/10.1371/journal.pone.0162368

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Chen LH, Wang YF, Xu QH, Chen SS (2018) Omega-3 fatty acids as a treatment for non-alcoholic fatty liver disease in children: A systematic review and meta-analysis of randomized controlled trials. Clin Nutr 37(2):516–521. https://doi.org/10.1016/j.clnu.2016.12.009

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, Bedogni G, Svegliati-Baroni G, Sofi F, Milani S, Abbate R, Surrenti C, Casini A (2006) Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 23(8):1143–1151. https://doi.org/10.1111/j.1365-2036.2006.02885.x

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW (2008) Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 14(41):6395–6400

    CAS  Article  Google Scholar 

  23. 23.

    Sofi F, Giangrandi I, Cesari F, Corsani I, Abbate R, Gensini GF, Casini A (2010) Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr 61(8):792–802. https://doi.org/10.3109/09637486.2010.487480

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Cazzola R, Russo-Volpe S, Miles EA, Rees D, Banerjee T, Roynette CE, Wells SJ, Goua M, Wahle KW, Calder PC, Cestaro B (2007) Age- and dose-dependent effects of an eicosapentaenoic acid-rich oil on cardiovascular risk factors in healthy male subjects. Atherosclerosis 193(1):159–167. https://doi.org/10.1016/j.atherosclerosis.2006.06.008

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Brunt EM (2010) Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7(4):195–203. https://doi.org/10.1038/nrgastro.20

    Article  PubMed  Google Scholar 

  26. 26.

    Scorletti E, Byrne CD (2013) Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease. Annu Rev Nutr 33:231–248. https://doi.org/10.1146/annurev-nutr-071812-161230

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Wahli W, Michalik L (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 23(7):351–363. https://doi.org/10.1016/j.tem.2012.05.001

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Khan SA, Ali A, Khan SA, Zahran SA, Damanhouri G, Azhar E, Qadri I (2014) Unraveling the complex relationship triad between lipids, obesity, and inflammation. Med Inflamm 2014:502749. https://doi.org/10.1155/2014/502749

    CAS  Article  Google Scholar 

  29. 29.

    Schaeffer L, Gohlke H, Muller M, Heid IM, Palmer LJ, Kompauer I, Demmelmair H, Illig T, Koletzko B, Heinrich J (2006) Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet 15(11):1745–1756. https://doi.org/10.1093/hmg/ddl117

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T, Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K, Osuga J, Gotoda T, Ishibashi S, Itaka K, Kataoka K, Nagai R, Yamada N, Kadowaki T, Shimano H (2010) Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. J Biol Chem 285(15):11681–11691. https://doi.org/10.1074/jbc.M109.096107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G (2010) Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des 16(17):1941–1951. https://doi.org/10.2174/138161210791208875

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Gonzalez-Periz A, Horrillo R, Ferre N, Gronert K, Dong B, Moran-Salvador E, Titos E, Martinez-Clemente M, Lopez-Parra M, Arroyo V, Claria J (2009) Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J 23(6):1946–1957. https://doi.org/10.1096/fj.08-125674

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Calder PC (2015) Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim Biophys Acta 1851(4):469–484. https://doi.org/10.1016/j.bbalip.2014.08.010

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Calder PC (2013) Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol 75(3):645–662. https://doi.org/10.1111/j.1365-2125.2012.04374.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Patterson AC, Metherel AH, Hanning RM, Stark KD (2014) The percentage of DHA in erythrocytes can detect non-adherence to advice to increase EPA and DHA intakes. Br J Nutr 111(2):270–278. https://doi.org/10.1017/s0007114513002225

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40(6):1387–1395. https://doi.org/10.1002/hep.20466

    Article  PubMed  Google Scholar 

  37. 37.

    Gong W, Liu A, Yao Y, Ma Y, Ding C, Song C, Yuan F, Zhang Y, Feng G, Chen Z, Ding G (2018) Nutrient supplement use among the chinese population: a Cross-Sectional Study of the 2010(-)2012 China Nutrition and Health Surveillance. Nutrients. https://doi.org/10.3390/nu10111733

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the participants and the coordination staff in the GNHS cohort study gratefully.

Funding

This study was supported by the National Science Foundation of China (No. 81472965, 81773416); the 5010 Program for Clinical Researches (No. 2007032) by the Sun Yat-sen University. The funders had no role in study design, collection, analysis and interpretation of data, writing of the report and in the decision to submit the article for publication.

Author information

Affiliations

Authors

Contributions

YMC conceived and designed the research; ZYC, ML, LPJ, MLX, HLD and GDC collected the data; ZYC performed the data analysis, ZYC and YMC wrote the paper; and YMC had primary responsibility for the final content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yu-ming Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, Z., Liu, M., Jing, L. et al. Erythrocyte membrane n-3 polyunsaturated fatty acids are inversely associated with the presence and progression of nonalcoholic fatty liver disease in Chinese adults: a prospective study. Eur J Nutr 59, 941–951 (2020). https://doi.org/10.1007/s00394-019-01953-2

Download citation

Keywords

  • Erythrocyte membrane
  • n-3 polyunsaturated fatty acids
  • Nonalcoholic fatty liver disease
  • Prospective study