Progress on the mechanism of food polyphenols in the prevention of liver fibrosis

Abstract

Liver fibrosis is the formation of extracellular matrix deposits due to excessive repair of chronic liver damage. Liver fibrosis is a necessary stage in the progression of cirrhosis, and timely intervention reverses the pathogenesis. Liver fibrosis is a dynamic and highly integrated molecular, cellular and organisational process. Currently, no specific drug is used to treat liver fibrosis, and liver transplantation is the main clinical treatment for cirrhosis. Chemical drugs are often designed to target individual genes or proteins, with kinds of side effects. Food polyphenols, which are available and safe, have unique advantages and great potential in the treatment with the liver fibrosis. This review summarizes the pathogenesis of liver fibrosis and provides examples of food polyphenols’ anti-liver fibrosis mechanisms that have been identified in recent studies, and provides some sights for the development of anti-liver fibrosis drugs.

Keywords

food polyphenols / liver fibrosis / mechanism

Acknowledgments

This work was supported by the People’s Livelihood Plan Project of Department of Science and Technology of Liaoning Province (No. 2021JH2/10300074); Department of Education of Liaoning Province (No. LJKMZ20221367); Career Development Support Plan for Young and Middleaged Teachers in Shenyang Pharmaceutical University (No. ZQN2018003).

References

[1] Man S, Deng Y, Ma Y, et al. Prevalence of liver steatosis and fibrosis in the general population and various high-risk populations: A nationwide study with 5.7 million adults in China[J]. Gastroenterology, 2023, 165 (4): 1025-1040.

[2] Zhang Z, Yuan Y, Hu L, et al. ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways[J]. Journal of Advanced Research, 2023, 47: 41-56.

[3] Zhuang Y, Ortega-Ribera M, Thevkar Nagesh P, et al. Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis- induced liver and kidney injury via regulation of ZBP1[J]. Hepatology, 2024, 79 (4): 752-767.

[4] Tsuchiya Y, Seki T, Kobayashi K, et al. Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis[J]. Nature Communications, 2023, 14 (1): 6304.

[5] He M, Chu T, Wang Z, et al. Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis[J]. Frontiers in Immunology, 2023, 14: 1147379.

[6] Roehlen N, Crouchet E, Baumert TF. Liver fibrosis: Mechanistic concepts and therapeutic perspectives[J]. Cells, 2020, 9 (4): 875.

[7] Abenavoli L, Milic N, Luzza F, et al. Polyphenols treatment in patients with nonalcoholic fatty liver disease[J]. Journal of Translational Internal Medicine, 2017, 5 (3): 144-147.

[8] Tsao R. Chemistry and biochemistry of dietary polyphenols[J]. Nutrients, 2010, 2 (12): 1231-1246.

[9] Newberry EP, Hall Z, Xie Y, et al. Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer[J]. Hepatology, 2021, 74 (3): 1203-1219.

[10] Yao L, Hu X, Dai K, et al. Mesenchymal stromal cells: Promising treatment for liver cirrhosis[J]. Stem Cell Research & Therapy, 2022, 13 (1): 308.

[11] Paquissi FC. Immunity and fibrogenesis: The role of Th17/ IL-17 axis in HBV and HCV-induced chronic hepatitis and progression to cirrhosis[J]. Frontiers in Immunology, 2017, 8: 1195.

[12] Meng F, Wang K, Aoyama T, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice[J]. Gastroenterology, 2012, 143 (3): 765-776.

[13] Tan Z, Qian X, Jiang R, et al. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation[J]. Journal of Immunology, 2013, 191 (4): 1835-1844.

[14] Fabre T, Kared H, Friedman SL, et al. IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK- dependent manner[J]. Journal of Immunology, 2014, 193 (8): 3925-3933.

[15] Wang Q, Zhou J, Zhang B, et al. Hepatitis B virus induces IL-23 production in antigen presenting cells and causes liver damage via the IL-23/IL-17 axis[J]. PLoS Pathogens, 2013, 9 (6): e1003410.

[16] Jiang Y, Zhang T, Kusumanchi P, et al. Alcohol metabolizing enzymes, microsomal ethanol oxidizing system, cytochrome P450 2E1, catalase, and aldehyde dehydrogenase in alcohol-associated liver disease[J]. Biomedicines, 2020, 8 (3): 50.

[17] Abenavoli L, Larussa T, Corea A, et al. Dietary polyphenols and non-alcoholic fatty liver disease[J]. Nutrients, 2021, 13 (2): 494.

[18] Day CP, James OF. Steatohepatitis: A tale of two “hits”?[J]. Gastroenterology, 1998, 114 (4): 842-845.

[19] Borrelli A, Bonelli P, Tuccillo FM, et al. Role of gut microbiota and oxidative stress in the progression of non- alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches[J]. Redox Biology, 2018, 15: 467-479.

[20] Fang YL, Chen H, Wang CL, et al. Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”[J]. World Journal of Gastroenterology, 2018, 24 (27): 2974-2983.

[21] Kim JY, Garcia-Carbonell R, Yamachika S, et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P[J]. Cell, 2018, 175 (1): 133-145.

[22] Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH: Postprandial lipid metabolism as a link between adiponectin and liver disease[J]. Hepatology, 2005, 42 (5): 1175-1183.

[23] Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Gastroenterology & Hepatology, 2021, 18 (3): 151-166.

[24] Han D, Kim H, Kim S, et al. Sestrin2 protects against cholestatic liver injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-mediated pyroptosis[J]. Experimental & Molecular Medicine, 2022, 54 (3): 239-251.

[25] Tian SY, Chen SM, Pan CX, et al. FXR: Structures, biology, and drug development for NASH and fibrosis diseases[J]. Acta Pharmacologica Sinica, 2022, 43 (5): 1120-1132.

[26] Meng F, Zong W, Wei X, et al. Dolomiaea souliei ethyl acetate extract protected against α-naphthylisothiocyanate- induced acute intrahepatic cholestasis through regulation of farnesoid x receptor-mediated bile acid metabolism[J]. Phytomedicine, 2021, 87: 153588.

[27] Abenavoli L, Izzo AA, Milić N, et al. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases[J]. Phytotherapy Research, 2018, 32 (11): 2202-2213.

[28] Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum)[J]. Integrative Cancer Therapies, 2007, 6 (2): 104-109.

[29] Wadhwa K, Pahwa R, Kumar M, et al. Mechanistic insights into the pharmacological significance of silymarin[J]. Molecules, 2022, 27 (16): 5327.

[30] Shaarawy SM, Tohamy AA, Elgendy SM, et al. Protective effects of garlic and silymarin on NDEA-induced rats hepatotoxicity[J]. International Journal of Biological Sciences, 2009, 5 (6): 549-557.

[31] Yang W, Liang Z, Wen C, et al. Silymarin protects against acute liver injury induced by acetaminophen by downregulating the expression and activity of the CYP2E1 enzyme[J]. Molecules, 2022, 27 (24): 8855.

[32] Zhu SY, Jiang N, Yang J, et al. Silybum marianum oil attenuates hepatic steatosis and oxidative stress in high fat diet-fed mice[J]. Biomedicine & Pharmacotherapy, 2018, 100: 191-197.

[33] Aghazadeh S, Amini R, Yazdanparast R, et al. Anti- apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis[J]. Experimental and Toxicologic Pathology, 2011, 63 (6): 569-574.

[34] Ou Q, Weng YY, Wang SW, et al. Silybin alleviates hepatic steatosis and fibrosis in NASH mice by inhibiting oxidative stress and involvement with the Nf-κB pathway[J]. Digestive Diseases and Sciences, 2018, 63 (12): 3398-3408.

[35] Zhang B, Xu D, She L, et al. Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease[J]. FASEB Journal, 2018, 32 (2): 757-767.

[36] Zhao X, Wang H, Yang Y, et al. Protective effects of silymarin against D-Gal/LPS-induced organ damage and inflammation in mice[J]. Drug Design, Development and Therapy, 2021, 15: 1903-1914.

[37] Tajik N, Tajik M, Mack I, et al. The potential effects of chlorogenic acid, the main phenolic components in coffee, on health: A comprehensive review of the literature[J]. European Journal of Nutrition, 2017, 56 (7): 2215-2244.

[38] Olthof MR, Hollman PC, Katan MB. Chlorogenic acid and caffeic acid are absorbed in humans[J]. The Journal of Nutrition, 2001, 131 (1): 66-71.

[39] Kim SH, Seo H, Kwon D, et al. Taurine ameliorates tunicamycin-induced liver injury by disrupting the vicious cycle between oxidative stress and endoplasmic reticulum stress[J]. Life (Basel, Switzerland), 2022, 12 (3): 354.

[40] Moslehi A, Komeili-Movahhed T, Ahmadian M, et al. Chlorogenic acid attenuates liver apoptosis and inflammation in endoplasmic reticulum stress-induced mice[J]. Iranian Journal of Basic Medical Sciences, 2023, 26 (4): 478-485.

[41] Ji L, Jiang P, Lu B, et al. Chlorogenic acid, a dietary polyphenol, protects acetaminophen-induced liver injury and its mechanism[J]. The Journal of Nutritional Biochemistry, 2013, 24 (11): 1911-1919.

[42] Shi H, Shi A, Dong L, et al. Chlorogenic acid protects against liver fibrosis in vivo and in vitro through inhibition of oxidative stress[J]. Clinical Nutrition, 2016, 35 (6): 1366-1373.

[43] Yang F, Luo L, Zhu ZD, et al. Chlorogenic acid inhibits liver fibrosis by blocking the miR-21-regulated TGF-β1/ Smad7 signaling pathway in vitro and in vivo[J]. Frontiers in Pharmacology, 2017, 8: 929.

[44] Khan N, Mukhtar H. Tea polyphenols in promotion of human health[J]. Nutrients, 2018, 11 (1): 39.

[45] Yang CS, Zhang J, Zhang L, et al. Mechanisms of body weight reduction and metabolic syndrome alleviation by tea[J]. Molecular Nutrition & Food Research, 2016, 60 (1): 160-174.

[46] Shi H, Zhao XH, Peng Q, et al. Green tea polyphenols alleviate di-(2-ethylhexyl) phthalate-induced liver injury in mice[J]. World Journal of Gastroenterology, 2023, 29 (34): 5054-5074.

[47] Yu DK, Zhang CX, Zhao SS, et al. The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway[J]. Acta Pharmacologica Sinica, 2015, 36 (4): 473-482.

[48] Wang L, Yang G, Yuan L, et al. Green tea catechins effectively altered hepatic fibrogenesis in rats by inhibiting ERK and Smad1/2 phosphorylation[J]. Journal of Agricultural and Food Chemistry, 2019, 67 (19): 5437-5445.

[49] Al-Basher GI. Green tea activity and iron overload induced molecular fibrogenesis of rat liver[J]. Saudi Journal of Biological Sciences, 2019, 26 (3): 531-540.

[50] Tian B, Liu J. Resveratrol: A review of plant sources, synthesis, stability, modification and food application[J]. Journal of the Science of Food and Agriculture, 2020, 100 (4): 1392-1404.

[51] Zhang LX, Li CX, Kakar MU, et al. Resveratrol (RV): A pharmacological review and call for further research[J]. Biomedecine & Pharmacotherapie, 2021, 143: 112164.

[52] Koushki M, Amiri-Dashatan N, Ahmadi N, et al. Resveratrol: A miraculous natural compound for diseases treatment[J]. Food Science & Nutrition, 2018, 6 (8): 2473-2490.

[53] Sales JM, Resurreccion AVA. Resveratrol in peanuts[J]. Critical Reviews in Food Science and Nutrition, 2014, 54 (6): 734-770.

[54] Wang Y, Sun X, Han X, et al. Resveratrol improves hepatic ischemia-reperfusion injury by inhibiting neutrophils via the ERK signaling pathway[J]. Biomedecine & Pharmacotherapie, 2023, 160: 114358.

[55] Zhu W, Chen S, Li Z, et al. Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice[J]. Nutrition & Metabolism, 2014, 11: 35.

[56] Moraes ACND, Andrade CBVD, Ramos IPR, et al. Resveratrol promotes liver regeneration in drug-induced liver disease in mice[J]. Food Research International, 2021, 142: 110185.

[57] Wang Y, Jiang Y, Fan X, et al. Hepato-protective effect of resveratrol against acetaminophen-induced liver injury is associated with inhibition of CYP-mediated bioactivation and regulation of SIRT1-p53 signaling pathways[J]. Toxicology Letters, 2015, 236 (2): 82-89.

[58] Che Y, Shi X, Zhong X, et al. Resveratrol prevents liver damage in MCD-induced steatohepatitis mice by promoting SIGIRR gene transcription[J]. The Journal of Nutritional Biochemistry, 2020, 82: 108400.

[59] Trepiana J, Milton-Laskibar I, Gómez-Zorita S, et al. Involvement of 5’-activated protein kinase (AMPK) in the effects of resveratrol on liver steatosis[J]. International Journal of Molecular Sciences, 2018, 19 (11): 3473.

[60] Ni Z, Bikadi Z, Rosenberg MF, et al. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2)[J]. Current Drug Metabolism, 2010, 11 (7): 603-617.

[61] Kurzawski M, Szeląg-Pieniek S, Łapczuk-Romańska J, et al. The reference liver - ABC and SLC drug transporters in healthy donor and metastatic livers[J]. Pharmacological Reports, 2019, 71 (4): 738-745.

[62] Zhang J, Ping J, Jiang N, et al. Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways[J]. Journal of Food Biochemistry, 2022, 46 (12): e14463.

[63] Hung WL, Hsiao YT, Chiou YS, et al. Hepatoprotective effect of piceatannol against carbon tetrachloride-induced liver fibrosis in mice[J]. Food & Function, 2021, 12 (22): 11229-11240.

[64] Jabczyk M, Nowak J, Hudzik B, et al. Curcumin in metabolic health and disease[J]. Nutrients, 2021, 13 (12): 4440.

[65] Abd El-Hack ME, El-Saadony MT, Swelum AA, et al. Curcumin, the active substance of turmeric: Its effects on health and ways to improve its bioavailability[J]. Journal of the Science of Food and Agriculture, 2021, 101 (14): 5747-5762.

[66] Kotha RR, Luthria DL. Curcumin: Biological, pharmaceutical, nutraceutical, and analytical aspects[J]. Molecules, 2019, 24 (16): 2930.

[67] Kong D, Zhang Z, Chen L, et al. Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy[J]. Redox Biology, 2020, 36: 101600.

[68] Zhao Y, Ma X, Wang J, et al. Curcumin protects against CCl4-induced liver fibrosis in rats by inhibiting HIF-1α through an ERK-dependent pathway[J]. Molecules, 2014, 19 (11): 18767-18780.

[69] Qin L, Qin J, Zhen X, et al. Curcumin protects against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis: A study in vitro and in vivo[J]. Biomedecine & Pharmacotherapie, 2018, 101: 599-607.

[70] Xiong ZE, Dong WG, Wang BY, et al. Curcumin attenuates chronic ethanol-induced liver injury by inhibition of oxidative stress via mitogen-activated protein kinase/nuclear factor E2-related factor 2 pathway in mice[J]. Pharmacognosy Magazine, 2015, 11 (44): 707-715.

[71] Farzaei MH, Zobeiri M, Parvizi F, et al. Curcumin in liver diseases: A systematic review of the cellular mechanisms of oxidative stress and clinical perspective[J]. Nutrients, 2018, 10 (7): 855.

[72] Wang W, Wang S, Liu Y, et al. Ellagic acid: A dietary- derived phenolic compound for drug discovery in mild cognitive impairment[J]. Frontiers in Aging Neuroscience, 2022, 14: 925855.

[73] García-Niño WR, Zazueta C. Ellagic acid : Pharmacological activities and molecular mechanisms involved in liver protection[J]. Pharmacological Research, 2015, 97: 84-103.

[74] Aslan A, Gok O, Erman O, et al. Ellagic acid impedes carbontetrachloride-induced liver damage in rats through suppression of NF-kB, Bcl-2 and regulating Nrf-2 and caspase pathway[J]. Biomedecine & Pharmacotherapie, 2018, 105: 662-669.

[75] Altamimi JZ, Alshammari GM, AlFaris NA, et al. Ellagic acid protects against non-alcoholic fatty liver disease in streptozotocin-diabetic rats by activating AMPK[J]. Pharmaceutical Biology, 2022, 60 (1): 25-37.

[76] Li L, Wang K, Jia R, et al. Ferroportin-dependent ferroptosis induced by ellagic acid retards liver fibrosis by impairing the SNARE complexes formation[J]. Redox Biology, 2022, 56: 102435.

[77] Kim DH, Sim Y, Hwang JH, et al. Ellagic acid prevents binge alcohol-induced leaky gut and liver injury through inhibiting gut dysbiosis and oxidative stress[J]. Antioxidants, 2021, 10 (9): 1386.

[78] Afifi NA, Ibrahim MA, Galal MK. Hepatoprotective influence of quercetin and ellagic acid on thioacetamide- induced hepatotoxicity in rats[J]. Canadian Journal of Physiology and Pharmacology, 2018, 96 (6): 624-629.

[79] Shendge AK, Basu T, Panja S, et al. An ellagic acid isolated from Clerodendrum viscosum leaves ameliorates iron-overload induced hepatotoxicity in Swiss albino mice through inhibition of oxidative stress and the apoptotic pathway[J]. Biomedecine & Pharmacotherapie, 2018, 106: 454-465.

[80] Dong M, Li L, Li G, et al. Mangiferin protects against alcoholic liver injury via suppression of inflammation- induced adipose hyperlipolysis[J]. Food & Function, 2020, 11 (10): 8837-8851.

[81] Zhang L, Liu C, Yin L, et al. Mangiferin relieves CCl4- induced liver fibrosis in mice[J]. Scientific Reports, 2023, 13 (1): 4172.

[82] Zhang XL, Zhang XY, Ge XQ, et al. Mangiferin prevents hepatocyte epithelial‐mesenchymal transition in liver fibrosis via targeting HSP27‐mediated JAK2/STAT3 and TGF‐β1/Smad pathway[J]. Phytotherapy Research, 2022, 36 (11): 4167-4182.

[83] Amer MA, Othman AI, El-Missiry MA, et al. Proanthocyanidins attenuated liver damage and suppressed fibrosis in CCl₄-treated rats[J]. Environmental Science and Pollution Research International, 2022, 29 (60): 91127-91138.

[84] Kong Y, Yan T, Tong Y, et al. Gut microbiota modulation by polyphenols from aronia melanocarpa of LPS-induced liver diseases in rats[J]. Journal of Agricultural and Food Chemistry, 2021, 69 (11): 3312-3325.

[85] Wang Z, Liu Y, Zhao X, et al. Aronia melanocarpa prevents alcohol-induced chronic liver injury via regulation of Nrf2 signaling in C57BL/6 mice[J]. Oxidative Medicine and Cellular Longevity, 2020, 2020: 4054520.

[86] Musolino V, Gliozzi M, Scarano F, et al. Bergamot polyphenols improve dyslipidemia and pathophysiological features in a mouse model of non-alcoholic fatty liver disease[J]. Scientific Reports, 2020, 10: 2565.

[87] Manna K, Khan ZS, Saha M, et al. Manjari medika grape seed extract protects methotrexate-induced hepatic inflammation: Involvement of NF-κB/NLRP3 and Nrf2/ HO-1 signaling system[J]. Journal of Inflammation Research, 2023, 16: 467-492.