Natural health products for treatment of metabolism dysfunction-associated steatotic liver disease

Main Article Content

Catherine B. Chan

Abstract

Metabolism dysfunction-associated steatotic liver disease affects approximately 30% of the world’s population, yet there is only one approved treatment option applicable to more advanced disease. Many individuals consume natural health products for general health and a variety of medical conditions but none are recommended for metabolism dysfunction-associated steatotic liver disease in current European or American guidelines. Nevertheless, human trials indicate that some of these products may be efficacious for treatment of metabolism dysfunction-associated steatotic liver disease and these are supported by mechanistic studies using animal models. This narrative review aims to highlight recent research in human and animal trials on selected natural health products. So far, neither probiotics nor omega-3 polyunsaturated fatty acids have produced convincing, consistent benefits in human randomized controlled trials although studies in mouse models suggest that they have actions can lead to reduction of hepatic steatosis or other markers, such as liver enzymes. Two of the many polyphenols that have been studied were also reviewed here. Trials with resveratrol in humans have not yielded significant results whereas curcumin, the active ingredient in turmeric, appeared to consistently lower steatosis or liver enzymes. Both compounds reduced steatosis in rodent models of MASLD, involving a variety of mechanisms including anti-oxidant, anti-inflammatory and metabolic effects. More, better-designed and powered human trials are required to provide convincing evidence of efficacy of most natural health products.

Keywords: Metabolism dysfunction-associated steatotic liver disease, Natural health products, Hepatic steatosis, Omega-3 polyunsaturated fatty acids, Probiotics, Polyphenols, Curcumin and resveratrol

Article Details

How to Cite
CHAN, Catherine B.. Natural health products for treatment of metabolism dysfunction-associated steatotic liver disease. Medical Research Archives, [S.l.], v. 12, n. 11, nov. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/6100>. Date accessed: 12 dec. 2024. doi: https://doi.org/10.18103/mra.v12i11.6100.
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Review Articles

References

1. Mishra S, Stierman B, Gahche JJ, N P. Dietary supplement use among adults: United States, 2017–2018. 2021. NCHS Data Brief, no 399.

2. Ipsos—European Public Affairs. Consumer survey on food supplements in the EU. 2022. https://foodsupplementseurope.org/wp-content/uploads/2022/07/FSE-Consumer_Survey-Ipsos-2022.pdf

3. Le MH, Yeo YH, Li X, et al. 2019 global NAFLD prevalence: A systematic review and meta-analysis. Clin Gastroenterol and Hepatol. 2022;20(12):2809-2817.e28. doi:10.1016/j.cgh.2021.12.002

4. Keam SJ. Resmetirom: First Approval. Drugs. Jun 2024;84(6):729-735. doi:10.1007/s40265-024-02045-0

5. Tacke F, Horn P, Wai-Sun Wong V, et al. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology. 2024;81(3):492-542. doi:10.1016/j.jh ep.2024.04.031

6. Rinella ME, Sookoian S. From NAFLD to MASLD: updated naming and diagnosis criteria for fatty liver disease. J Lipid Res. Jan 2024;65(1):100485. doi:10.1016/j.jlr.2023.100485

7. Li L, Liu DW, Yan HY, Wang ZY, Zhao SH, Wang B. Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies. Obes Rev. Jun 2016;17(6):510-9. doi:10.1111/obr.12407

8. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801. doi:10.1016/j.jhep.2019.06.021

9. Quek J, Chan KE, Wong ZY, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023 ;8(1):20-30. doi:10.1016/S2468-1253(22)00317-X

10. Park HJ, Lee S, Lee JS. Differences in the prevalence of NAFLD, MAFLD, and MASLD according to changes in the nomenclature in a health check-up using MRI-derived proton density fat fraction. Abdom Radiol (NY). Sep 2024;49(9):30 36-3044. doi:10.1007/s00261-024-04285-w

11. Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci. Sep 2018;75(18):3313-3327. doi:10.1007/s00018-018-2860-6

12. Green CJ, Hodson L. The influence of dietary fat on liver fat accumulation. Nutrients. Nov 10 2014;6(11):5018-33. doi:10.3390/nu6115018

13. Longo M, Zatterale F, Naderi J, et al. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int J Mol Sci. May 13 2019;20(9)doi:10.3390/ijms20092358

14. Tilg H, Adolph TE, Moschen AR. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: Revisited after a decade. Hepatology. Feb 2021;73(2):833-842. doi:10.1002/hep.31518

15. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. Aug 2016;65(8) :1038-48. doi:10.1016/j.metabol.2015.12.012

16. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol. Sep 2021;18(9):599-612. doi:10.1038/s41575-021-00448-y

17. Abushamat LA, Shah PA, Eckel RH, Harrison SA, Barb D. The emerging fole of glucagon-like peptide-1 receptor agonists for the treatment of metabolic dysfunction-associated steatohepatitis. Clinical Gastroenterology and Hepatology. 2024; 22(8):1565-1574. doi:10.1016/j.cgh.2024.01.032

18. Hill AL, Khan M, Kiani AZ, et al. Global liver transplantation: emerging trends and ethical challenges. Langenbecks Arch Surg. Oct 25 2023; 408(1):418. doi:10.1007/s00423-023-03144-4

19. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. Jan 2018;67(1):328-357. doi:10.1002/ hep.29367

20. Sharma M, Premkumar M, Kulkarni AV, Kumar P, Reddy DN, Rao NP. Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail. J Clin Transl Hepatol. Feb 28 2021;9(1):40-50. doi:10.14218/JCTH.2020.00055

21. Tincopa MA, Anstee QM, Loomba R. New and emerging treatments for metabolic dysfunction-associated steatohepatitis. Cell Metabolism. 2024; 36(5):912-926. doi:10.1016/j.cmet.2024.03.011

22. Natural Health Products Regulations (Government of Canada) 84 pp (2024).

23. Public Health. Herbal medicinal products. Directorate-General for Health and Food Safety, European Commission. https://health.ec.europa.eu/medicinal-products/herbal-medicinal-products_en

24. von Wright A. Regulating the safety of probiotics--the European approach. Curr Pharm Des. 2005;11(1):17-23. doi:10.2174/1381612053382322

25. How the European Commission deals with 'health claims' concerning probiotics included in foodstuffs, (2023). Accessed September 6, 2024. https://www.ombudsman.europa.eu/en/opening-summary/en/179398

26. Sapere. International approaches to Natural Health Product regulations: regulatory scan. 2024. Accessed September 6, 2024. https://www.health.govt.nz/publications/international-approaches-to-natural-health-product-regulations

27. Office of Dietary Supplements. Probiotics: Fact Sheet for Health Professionals. National Institutes of Health. Accessed September 6, 2024,

28. Komolafe O, Buzzetti E, Linden A, et al. Nutritional supplementation for nonalcohol-related fatty liver disease: a network meta-analysis. Cochrane Database Syst Rev. Jul 19 2021;7(7):Cd 013157. doi:10.1002/14651858.CD013157.pub2

29. Rong L, Ch'ng D, Jia P, Tsoi KKF, Wong SH, Sung JJY. Use of probiotics, prebiotics, and synbiotics in non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. Oct 2023;38(10):1682-1694. doi:10.1111/ jgh.16256

30. Zhu Y, Tan JK, Liu J, Goon JA. Roles of Traditional and Next-Generation Probiotics on Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH): A Systematic Review and Network Meta-Analysis. Antioxidants. 2024;13(3):329.

31. Carpi RZ, Barbalho SM, Sloan KP, et al. The Effects of Probiotics, Prebiotics and Synbiotics in Non-Alcoholic Fat Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH): A Systematic Review. Int J Mol Sci. Aug 8 2022;23(15)doi:10.33 90/ijms23158805

32. Theodoridis X, Kalopitas G, Vadarlis A, et al. Comparative efficacy of different treatment modalities in the management of pediatric non-alcoholic fatty liver disease: A systematic review and network meta-analysis. Pharmacol Ther. Dec 2022;240:108294. doi:10.1016/j.pharmthera.2022.108294

33. Sun C, Xiong X, Liu M, et al. Bacteroides ovatus alleviates high-fat and high-cholesterol -induced nonalcoholic fatty liver disease via gut-liver axis. Biomed Pharmacother. Sep 2024;178:11 7156. doi:10.1016/j.biopha.2024.117156

34. Kim H, Lee K, Kim JY, et al. Lactobacillus helveticus Isolated from Raw Milk Improves Liver Function, Hepatic Steatosis, and Lipid Metabolism in Non-Alcoholic Fatty Liver Disease Mouse Model. Microorganisms. Sep 30 2023;11(10)doi:10.3390/ microorganisms11102466

35. Nian F, Wu L, Xia Q, Tian P, Ding C, Lu X. Akkermansia muciniphila and Bifidobacterium bifidum Prevent NAFLD by Regulating FXR Expression and Gut Microbiota. J Clin Transl Hepatol. Aug 28 2023;11(4):763-776. doi:10.142 18/jcth.2022.00415

36. Kanmani P, Villena J, Lim SK, Song EJ, Nam YD, Kim H. Immunobiotic Bacteria Attenuate Hepatic Fibrosis through the Modulation of Gut Microbiota and the Activation of Aryl-Hydrocarbon Receptors Pathway in Non-Alcoholic Steatohepatitis Mice. Mol Nutr Food Res. Jul 2024;68(14):e24 00227. doi:10.1002/mnfr.202400227

37. Han Y, Li L, Wang B. Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives. Front Med. Oct 2022;16(5):667-685. doi:10.1007/s11684-022-0960-z

38. Jan T, Negi R, Sharma B, et al. Next generation probiotics for human health: An emerging perspective. Heliyon. Aug 30 2024;10(16):e35980. doi:10.1016/j.heliyon.2024.e35980

39. Rana A, Samtiya M, Dhewa T, Mishra V, Aluko RE. Health benefits of polyphenols: A concise review. J Food Biochem. Oct 2022;46(10):e14264. doi:10.1111/jfbc.14264

40. Wang X, Qi Y, Zheng H. Dietary Polyphenol, Gut Microbiota, and Health Benefits. Antioxidants (Basel). Jun 20 2022;11(6)doi:10.3390/antiox11061212

41. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. Jun 2008;65(11):1631-52. doi:10.1007/s00018-008-7452-4

42. Yang K, Chen J, Zhang T, et al. Efficacy and safety of dietary polyphenol supplementation in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. Front Immunol. 2022;13:949746. doi:10.3389/fimmu.2022.949746

43. Ngu MH, Norhayati MN, Rosnani Z, Zulkifli MM. Curcumin as adjuvant treatment in patients with non-alcoholic fatty liver (NAFLD) disease: A systematic review and meta-analysis. Complement Ther Med. Sep 2022;68:102843. doi:10.1016/j. ctim.2022.102843

44. Um MY, Hwang KH, Ahn J, Ha TY. Curcumin attenuates diet-induced hepatic steatosis by activating AMP-activated protein kinase. Basic Clin Pharmacol Toxicol. Sep 2013;113(3):152-7. doi:10. 1111/bcpt.12076

45. Afrin R, Arumugam S, Rahman A, et al. Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation. Int Immunopharmacol. Mar 2017;44:174-182. doi:10.1016/j.intimp.2017.01.016

46. Vizzutti F, Provenzano A, Galastri S, et al. Curcumin limits the fibrogenic evolution of experimental steatohepatitis. Lab Invest. Jan 2010; 90(1):104-15. doi:10.1038/labinvest.2009.112

47. Kuo JJ, Chang HH, Tsai TH, Lee TY. Positive effect of curcumin on inflammation and mitochondrial dysfunction in obese mice with liver steatosis. Int J Mol Med. Sep 2012;30(3):673-9. doi:10.3892/ijmm.2012.1049

48. Li X, Chen W, Ren J, et al. Effects of curcumin on non-alcoholic fatty liver disease: A scientific metrogy study. Phytomedicine. 2024/01/01/ 2024; 123:155241.doi:https://doi.org/10.1016/j.phymed.2023.155241

49. Han X-q, Xu S-q, Lin J-g. Curcumin Recovers Intracellular Lipid Droplet Formation Through Increasing Perilipin 5 Gene Expression in Activated Hepatic Stellate Cells In Vitro. Current Medical Science. 2019/10/01 2019;39(5):766-777. doi:10.1 007/s11596-019-2104-5

50. Feng D, Zou J, Su D, et al. Curcumin prevents high-fat diet-induced hepatic steatosis in ApoE(-/-) mice by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-κB inflammation. Nutr Metab (Lond). 2019;16:79. doi: 10.1186/s12986-019-0410-3

51. Li S, You J, Wang Z, et al. Curcumin alleviates high-fat diet-induced hepatic steatosis and obesity in association with modulation of gut microbiota in mice. Food Research International. 2021/05/01/ 20 21;143:110270.doi:https://doi.org/10.1016/j.foodres.2021.110270

52. Srinivas AN, Suresh D, Chidambaram SB, Santhekadur PK, Kumar DP. Apoptosis antagonizing transcription factor-mediated liver damage and inflammation to cancer: Therapeutic intervention by curcumin in experimental metabolic dysfunction associated steatohepatitis-hepatocellular carcinoma. J Cell Physiol. Jan 2024;239(1):135-151. doi:10.1002/jcp.31151

53. Hu RW, Carey EJ, Lindor KD, Tabibian JH. Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications. Ann Hepatol. November-December 2017;16(6):835-841. doi:10. 5604/01.3001.0010.5273

54. Lee ES, Kwon MH, Kim HM, Woo HB, Ahn CM, Chung CH. Curcumin analog CUR5-8 ameliorates nonalcoholic fatty liver disease in mice with high-fat diet-induced obesity. Metabolism. Feb 2020; 103:154015. doi:10.1016/j.metabol.2019.154015

55. Yang L-C, Wang C-C, Lee D-Y, et al. 4,4-Diallyl curcumin bis(2,2-hydroxymethyl)propanoate ameliorates nonalcoholic steatohepatitis in methionine-choline-deficient diet and Western diet mouse models. Chemical Biology & Drug Design. 2024;103(5):e14532.doi:https://doi.org/10.1111/cbdd.14532

56. Yang JW, Yeo HK, Yun JH, Lee JU. Theracurmin (Highly Bioavailable Curcumin) Prevents High Fat Diet-Induced Hepatic Steatosis Development in Mice. Toxicol Res. Oct 2019;35(4): 403-410. doi:10.5487/tr.2019.35.4.403

57. Maradana MR, Yekollu SK, Zeng B, et al. Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis. Metabolism. 2018/01/01/ 2018;78: 80-94. doi:https://doi.org/10.1016/j.metabol.2017.09.002

58. Aguirre L, Portillo MP, Hijona E, Bujanda L. Effects of resveratrol and other polyphenols in hepatic steatosis. World J Gastroenterol. Jun 21 2014;20(23):7366-80. doi:10.3748/wjg.v20.i23.7366

59. Catalgol B, Batirel S, Taga Y, Ozer NK. Resveratrol: French paradox revisited. Front Pharmacol. 2012;3:141. doi:10.3389/fphar.2012.00141

60. Wang GL, Fu YC, Xu WC, Feng YQ, Fang SR, Zhou XH. Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem Biophys Res Commun. Mar 13 2009;380(3):644-9. doi:10.1016/j.bbrc.200 9.01.163

61. Colak Y, Ozturk O, Senates E, et al. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med Sci Monit. May 2011;17(5):Hy5-9. doi:10.12659/msm.881749

62. Zhou R, Yi L, Ye X, et al. Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism. Cell Physiol Biochem. 2018;51(5):2397-2420. doi: 10.1159/000495898

63. Kong L, An X, Hu L, et al. Resveratrol ameliorates nutritional steatohepatitis through the mmu‑miR‑599/PXR pathway. Int J Mol Med. Apr 2022;49(4)doi:10.3892/ijmm.2022.5102

64. Che Y, Shi X, Zhong X, et al. Resveratrol prevents liver damage in MCD-induced steatohepatitis mice by promoting SIGIRR gene transcription. J Nutr Biochem. Aug 2020;82:1084 00. doi:10.1016/j.jnutbio.2020.108400

65. Li L, Hai J, Li Z, et al. Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol. Jan 2014;63:166-73. doi:10.1016/j. fct.2013.08.036

66. Andrade JM, Paraíso AF, de Oliveira MV, et al. Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition. Jul-Aug 2014;30(7-8):915-9. doi:10.1016 /j.nut.2013.11.016

67. Yang SJ, Lim Y. Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism. May 2014;63(5):693-701. doi:10.1016/j.metabol.2014.02.003

68. Yuan W, Zhang M, Wang C, et al. Resveratrol attenuates HFD-induced hepatic lipotoxicity by up-regulating Bmi-1 expression. Journal of Pharmacology and Experimental Therapeutics. 2022:JPET-AR-2021-001018. doi:10.1124/jpet.121.001018

69. Kessoku T, Imajo K, Honda Y, et al. Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Scientific reports. Feb 25 2016;6:22251. doi:10.1038/srep22251

70. Hosseini H, Teimouri M, Shabani M, et al. Resveratrol alleviates non-alcoholic fatty liver disease through epigenetic modification of the Nrf2 signaling pathway. Int J Biochem Cell Biol. Feb 2020;119:105667. doi:10.1016/j.biocel.2019.105667

71. Wang P, Wang J, Li D, Ke W, Chen F, Hu X. Targeting the gut microbiota with resveratrol: a demonstration of novel evidence for the management of hepatic steatosis. J Nutr Biochem. Jul 2020;81:108363. doi:10.1016/j.jnutbio.2020.108363

72. Zhang Y, Chen ML, Zhou Y, et al. Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res. Aug 2015;59(8):1443-57. doi:10.1002/ mnfr.201500016

73. Ji G, Wang Y, Deng Y, Li X, Jiang Z. Resveratrol ameliorates hepatic steatosis and inflammation in methionine/ choline-deficient diet-induced steatohepatitis through regulating autophagy. Lipids Health Dis. Oct 24 2015;14:134. doi:10.1186 /s12944-015-0139-6

74. Li X, Chen X-X, Xu Y, et al. Construction of Glycogen-Based Nanoparticles Loaded with Resveratrol for the Alleviation of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease. Biomacromolecules. 2022/01/10 2022;23(1):409-423. doi:10.1021/acs.biomac.1c01360

75. Teng W, Zhao L, Yang S, et al. The hepatic-targeted, resveratrol loaded nanoparticles for relief of high fat diet-induced nonalcoholic fatty liver disease. J Control Release. Aug 10 2019;307:139-149. doi:10.1016/j.jconrel.2019.06.023

76. Omega-3 fatty acids (National Institutes of Health) (2023).

77. Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. Oct 2007;46(4):1081-90. doi:10.1002/ hep.21763

78. Chen LH, Wang YF, Xu QH, Chen SS. 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. Apr 2018;37(2):516-521. doi:10.1016/j.clnu. 2016.12.009

79. Musa-Veloso K, Venditti C, Lee HY, et al. Systematic review and meta-analysis of controlled intervention studies on the effectiveness of long-chain omega-3 fatty acids in patients with nonalcoholic fatty liver disease. Nutr Rev. Aug 1 2018;76(8):581-602. doi:10.1093/nutrit/nuy022

80. Yang J, Fernández-Galilea M, Martínez-Fernández L, et al. Oxidative Stress and Non-Alcoholic Fatty Liver Disease: Effects of Omega-3 Fatty Acid Supplementation. Nutrients. 2019;11(4):872.

81. Musazadeh V, Karimi A, Malekahmadi M, Ahrabi SS, Dehghan P. Omega-3 polyunsaturated fatty acids in the treatment of non-alcoholic fatty liver disease: An umbrella systematic review and meta-analysis. Clin Exp Pharmacol Physiol. May 2023;50(5):327-334. doi:10.1111/1440-1681.13750

82. Deng M, Wen Y, Yan J, et al. Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials. BMC Med. Nov 16 2023;21(1): 447. doi:10.1186/s12916-023-03129-6

83. de Castro GS, Calder PC. Non-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids. Clin Nutr. Feb 2018;37(1):37-55. doi:10.1016/j.clnu.2017.01.006

84. Depner CM, Torres-Gonzalez M, Tripathy S, Milne G, Jump DB. Menhaden oil decreases high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese Ldlr-/- mice. J Nutr. Aug 2012;142(8):1495-503. doi:10. 3945/jn.112.158865

85. Tapia G, Valenzuela R, Espinosa A, et al. N-3 long-chain PUFA supplementation prevents high fat diet induced mouse liver steatosis and inflammation in relation to PPAR-α upregulation and NF-κB DNA binding abrogation. Mol Nutr Food Res. Jun 2014;58(6):1333-41. doi:10.1002/ mnfr.201300458

86. Dossi CG, Tapia GS, Espinosa A, Videla LA, D'Espessailles A. Reversal of high-fat diet-induced hepatic steatosis by n-3 LCPUFA: role of PPAR-α and SREBP-1c. J Nutr Biochem. Sep 2014;25(9):97 7-84. doi:10.1016/j.jnutbio.2014.04.011

87. Soni NK, Nookaew I, Sandberg AS, Gabrielsson BG. Eicosapentaenoic and docosahexaenoic acid-enriched high fat diet delays the development of fatty liver in mice. Lipids Health Dis. Jul 22 2015;14:74. doi:10.1186/s12944-015-0072-8

88. Valenzuela R, Espinosa A, González-Mañán D, et al. N-3 long-chain polyunsaturated fatty acid supplementation significantly reduces liver oxidative stress in high fat induced steatosis. PLoS One. 2012;7(10):e46400. doi:10.1371/journal.pon e.0046400

89. Delarue J, Lallès JP. Nonalcoholic fatty liver disease: Roles of the gut and the liver and metabolic modulation by some dietary factors and especially long-chain n-3 PUFA. Mol Nutr Food Res. Jan 2016;60(1):147-59. doi:10.1002/mnfr. 201500346

90. Hernández-Rodas MC, Valenzuela R, Echeverría F, et al. Supplementation with Docosahexaenoic Acid and Extra Virgin Olive Oil Prevents Liver Steatosis Induced by a High-Fat Diet in Mice through PPAR-α and Nrf2 Upregulation with Concomitant SREBP-1c and NF-kB Downregulation. Mol Nutr Food Res. Dec 2017;61(12)doi:10.1002/mnfr.201700479

91. Valenzuela R, Videla LA. Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View. Nutrients. Feb 15 2020;12(2)doi:10.3390/nu12020499

92. Echeverría F, Valenzuela R, Bustamante A, et al. High-fat diet induces mouse liver steatosis with a concomitant decline in energy metabolism: attenuation by eicosapentaenoic acid (EPA) or hydroxytyrosol (HT) supplementation and the additive effects upon EPA and HT co-administration. Food Funct. Sep 1 2019;10(9):6170 -6183. doi:10.1039/c9fo01373c

93. Sabinari I, Horakova O, Cajka T, Kleinova V, Wieckowski MR, Rossmeisl M. Influence of Lipid Class Used for Omega-3 Fatty Acid Supplementation on Liver Fat Accumulation in MASLD. Physiol Res. Aug 31 2024;73(Suppl 1):S29 5-s320. doi:10.33549/physiolres.935396

94. Van Herck MA, Vonghia L, Francque SM. Animal Models of Nonalcoholic Fatty Liver Disease-A Starter's Guide. Nutrients. Sep 27 2017;9(10)doi:10.3390/nu9101072