Fisetin as a Promising Agent in Non-Alcoholic Fatty Liver Disease: Insights into Pathogenic Mechanisms and Therapeutic Potential
-
Mahboobe Sattari
,
Kosar Ostadmohammadi
,
Hajar Hajian
,
Amin Karimpour
,
Fahime Sedghgou
,
Mohadese Sattari
,
Ghodratollah Panahi
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a widespread liver condition characterized by fat accumulation in the liver, with its development involving intricate processes such as inflammation, oxidative damage, and lipid metabolism disturbances. Current treatment options are limited, emphasizing the need for multi-targeted approaches that can simultaneously address these pathogenic pathways to improve liver health. This review synthesizes current evidence on how fisetin impacts molecular pathways relevant to NAFLD. It focuses on its effects in reducing inflammation, oxidative stress, and lipid accumulation, based on experimental and clinical studies examining gene expression, enzyme activity, and signaling pathways involved in hepatic steatosis and injury. This review examines the mechanisms by which fisetin intervention influences NAFLD management. It emphasizes glycemic control through post-prandial glucose reduction, mitigation of insulin resistance, improvements in pancreatic insulin secretion, and suppression of hepatic gluconeogenesis and glycogenolysis. Additionally, fisetin exerts plasma lipid-lowering effects via enhancement of hepatic β-oxidation and reduction of lipogenesis. The anti-inflammatory effects are observed both systemically and locally within the liver. Fisetin also enhances antioxidant defenses by activating antioxidant enzymes, reducing superoxide levels, chelating metal ions, and scavenging free radicals. Furthermore, fisetin modulates endoplasmic reticulum (ER) stress and promotes autophagy, contributing to the amelioration of NAFLD pathology. Taken together, Fisetin exhibits a promising hepatoprotective profile and may serve as a beneficial natural supplement for liver health. Its potential benefits in reducing liver steatosis and supporting NAFLD management, combined with its minimal side effects, make it an attractive candidate for further exploration as a complementary therapy.
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6. Wang Z, Du H, Zhao Y, Ren Y, Ma C, Chen H, et al. Response to pioglitazone in non-alcoholic fatty liver disease patients with vs. without type 2 diabetes: A meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne). 2023;14:1111430. https://doi.org/10.3389/fendo.2023.1111430
7. Akhtar DH, Iqbal U, Vazquez-Montesino LM, Dennis BB, Ahmed A. Pathogenesis of Insulin Resistance and Atherogenic Dyslipidemia in Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol. 2019;7(4):362-70. https://doi.org/10.14218/jcth.2019.00028
8. Fujita K, Nozaki Y, Wada K, Yoneda M, Fujimoto Y, Fujitake M, et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology. 2009;50(3):772-80. https://doi.org/10.1002/hep.23094
9. Luci C, Bourinet M, Leclère PS, Anty R, Gual P. Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies. Front Endocrinol (Lausanne). 2020;11:597648. https://doi.org/10.3389/fendo.2020.597648
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11. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest. 2003;83(5):655-63. https://doi.org/10.1097/01.lab.0000069036.63405.5c
12. Chen Z, Tian R, She Z, Cai J, Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med. 2020;152:116-41. https://doi.org/10.1016/j.freeradbiomed.2020.02.025
13. Čolak E, Pap D. The role of oxidative stress in the development of obesity and obesity-related metabolic disorders. J Med Biochem. 2021;40(1):1-9. https://doi.org/10.5937/jomb0-24652
14. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 Suppl):S47-64. https://doi.org/10.1016/j.jhep.2014.12.012
15. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest. 2009;119(5):1201-15. https://doi.org/10.1172/jci37007
16. Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(7):1768-76. https://doi.org/10.3748/wjg.v20.i7.1768
17. Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ. Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab. 2010;298(5):E1027-35. https://doi.org/10.1152/ajpendo.00642.2009
18. Soleimani AA, Sarajar BO, Aliabadi M, Azmon M, Meshkani R. A review of the therapeutic effects of polyphenols on non-alcoholic fatty liver disease: Focus on oxidative stress. Acta Biochim Iran. 2024. https://doi.org/10.18502/abi.v2i1.16242
19. Gómez-Virgilio L, Silva-Lucero MD, Flores-Morelos DS, Gallardo-Nieto J, Lopez-Toledo G, Abarca-Fernandez AM, et al. Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators. Cells. 2022;11(15). https://doi.org/10.3390/cells11152262
20. Jahangard R, Ebrahimi SSS, Vatannejad A, Meshkani R. Autophagy protects peripheral blood mononuclear cells from high glucose-induced inflammation and apoptosis. Acta Biochim Iran. 2023;1(1):40-9. https://doi.org/10.18502/abi.v1i1.14064
21. Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018;20(3):233-42. https://doi.org/10.1038/s41556-018-0037-z
22. Alves-Bezerra M, Cohen DE. Triglyceride Metabolism in the Liver. Compr Physiol. 2017;8(1):1-8. https://doi.org/10.1002/cphy.c170012
23. Raza S, Rajak S, Yen PM, Sinha RA. Autophagy and hepatic lipid metabolism: mechanistic insight and therapeutic potential for MASLD. npj metab health dis. 2024;2(1):19. https://doi.org/10.1038/s44324-024-00022-5
24. Zhang S, Peng X, Yang S, Li X, Huang M, Wei S, et al. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis. 2022;13(2):132. https://doi.org/10.1038/s41419-022-04593-3
25. Lavallard VJ, Gual P. Autophagy and non-alcoholic fatty liver disease. Biomed Res Int. 2014;2014:120179. https://doi.org/10.1155/2014/120179
26. Zhao Y, Zhou Y, Wang D, Huang Z, Xiao X, Zheng Q, et al. Mitochondrial Dysfunction in Metabolic Dysfunction Fatty Liver Disease (MAFLD). Int J Mol Sci. 2023;24(24). https://doi.org/10.3390/ijms242417514
27. Williams JA, Ni HM, Ding Y, Ding WX. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol. 2015;309(5):G324-40. https://doi.org/10.1152/ajpgi.00108.2015
28. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell metab. 2010;11(6):467-78. https://doi.org/10.1016/j.cmet.2010.04.005
29. Ghahremani H, Bahramzadeh A, Bolandnazar K, Emamgholipor S, Hosseini H, Meshkani R. Resveratrol as a potential protective compound against metabolic inflammation. Acta Biochim Iran. 2023;1(2):50-64. https://doi.org/10.18502/abi.v1i2.14101
30. Chahkandi S, Dabiri R, Mirmohammadkhani M, Amiri-Dashatan N, Koushki M. The effect of silymarin on liver enzymes and serum lipid profiles in Iranian patients with non-alcoholic fatty liver disease: A double-blind randomized controlled trial. Acta Biochim Iran. 2023. https://doi.org/10.18502/abi.v1i2.14105
31. Grynkiewicz G, Demchuk OM. New Perspectives for Fisetin. Front Chem. 2019;7:697. https://doi.org/10.3389/fchem.2019.00697
32. Shen B, Shangguan X, Yin Z, Wu S, Zhang Q, Peng W, et al. Inhibitory Effect of Fisetin on α-Glucosidase Activity: Kinetic and Molecular Docking Studies. Molecules. 2021;26(17). https://doi.org/10.3390/molecules26175306
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| Files | ||
| Issue | Vol 2 No 4 (2024) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/abi.v2i4.19106 | |
| Keywords | ||
| Fisetin NAFLD Hepatoprotection Natural Compound Mechanism of Action | ||
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How to Cite
1.
Sattari M, Ostadmohammadi K, Hajian H, Karimpour A, Sedghgou F, Sattari M, Panahi G. Fisetin as a Promising Agent in Non-Alcoholic Fatty Liver Disease: Insights into Pathogenic Mechanisms and Therapeutic Potential. ABI. 2024;2(4):186-195.
