表没食子儿茶素没食子酸酯预防并改善非酒精性脂肪性肝病的作用机制及研究进展

doi:10.13305/j.cnki.jts.2024.04.003

摘要/Abstract

摘要： 非酒精性脂肪性肝病（Nonalcoholic fatty liver disease,NAFLD）发病率逐年升高,目前尚无特效药物。绿茶的有效成分表没食子儿茶素没食子酸酯（Epigallocatechin gallate,EGCG）在低剂量范围内已被证明对NAFLD具有良好的改善作用。综述总结了EGCG通过抗氧化应激、抗炎、抑制铁死亡、减少脂质生成、调节自噬、调节肠道菌群以及降低胆汁酸代谢等方面延缓NAFLD发生发展的部分机制,以期为改善NAFLD的深入研究提供启示。

关键词: 非酒精性脂肪性肝病, 表没食子儿茶素没食子酸酯, 氧化应激, 炎症

Abstract: The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing year by year and there is no specific drug available. The active ingredient of green tea, epigallocatechin gallate (EGCG), has been widely proven to have a favorable ameliorative effect on NAFLD in the low dose range. Some of the mechanisms by which EGCG delays the development of NAFLD through anti-oxidative stress, anti-inflammation, inhibition of iron death, reduction of lipogenesis, up-regulation of autophagy, modulation of intestinal flora, and reduction of bile acid metabolism were summarized in this paper, so as to provide insights for in-depth research on improving NAFLD.

Key words: nonalcoholic fatty liver disease, epigallocatechin gallate, oxidative stress, inflammation

中图分类号:

陈佳欣, 张锦佳, 左会灵, 焦宇航, 石安华. 表没食子儿茶素没食子酸酯预防并改善非酒精性脂肪性肝病的作用机制及研究进展[J]. 茶叶科学, 2024, 44(4): 543-553. doi: 10.13305/j.cnki.jts.2024.04.003.

CHEN Jiaxin, ZHANG Jinjia, ZUO Huiling, JIAO Yuhang, SHI Anhua. The Mechanism and Research Progress of Epigallocatechin Gallate in Improving Non-alcoholic Fatty Liver Disease[J]. Journal of Tea Science, 2024, 44(4): 543-553. doi: 10.13305/j.cnki.jts.2024.04.003.

参考文献

[1] Boccatonda A, Andreetto L, D’Ardes D, et al. From NAFLD to MAFLD: definition, pathophysiological basis and cardiovascular implications[J]. Biomedicines, 2023, 11(3): 883. doi: 10.3390/biomedicines11030883.
[2] Younossi Z M, Golabi P, Paik J M, et al.The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review[J]. Hepatology, 2023, 77(4): 1335-1347.
[3] Williams C D, Stengel J, Asike M I, et al.Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study[J]. Gastroenterology, 2011, 140(1): 124-131.
[4] Rajak S, Raza S, Tewari A, et al.Environmental toxicants and NAFLD: a neglected yet significant relationship[J]. Digestive Diseases and Sciences, 2022, 67(8): 3497-3507.
[5] Van De Wier B, Koek G H, Bast A, et al. The potential of flavonoids in the treatment of non-alcoholic fatty liver disease[J]. Critical Reviews in Food Science and Nutrition, 2017, 57(4): 834-855.
[6] 陈红霞, 孟忠吉. 绿茶在非酒精性脂肪肝病治疗中的作用研究进展[J]. 江苏预防医学, 2014, 25(4): 44-47.
Chen H X, Meng Z J.Progress in the study of the role of green tea in the treatment of nonalcoholic fatty liver disease[J]. Jiangsu Journal of Preventive Medicine, 2014, 25(4): 44-47.
[7] 蒋华军. EGCG干预非酒精性脂肪肝大鼠代谢组学研究[D]. 长沙: 湖南农业大学, 2013.
Jiang H J.The metabonomics study on nonalcoholic fat liver disease in rat interfered by EGCG [D]. Changsha: Hunan Agricultural University, 2013.
[8] Pezeshki A, Safi S, Feizi A, et al.The effect of green tea extract supplementation on liver enzymes in patients with nonalcoholic fatty liver disease[J]. International Journal of Preventive Medicine, 2016, 7(1): 28. doi: 10.4103/2008-7802.173051.
[9] Almatroodi S A, Alsahli M A, Alharbi H M, et al.Epigallocatechin-3-gallate (EGCG), an active constituent of green tea: implications in the prevention of liver injury induced by diethylnitrosamine (DEN) in rats[J]. Applied Sciences, 2019, 9(22): 4821. doi: 10.3390/app9224821.
[10] Du Y, Paglicawan L, Soomro S, et al.Epigallocatechin-3-gallate dampens non-alcoholic fatty liver by modulating liver function, lipid profile and macrophage polarization[J]. Nutrients, 2021, 13(2): 599. doi: 10.3390/nu13020599.
[11] Gan L, Meng Z J, Xiong R B, et al.Green tea polyphenol epigallocatechin-3-gallate ameliorates insulin resistance in non-alcoholic fatty liver disease mice[J]. Acta Pharmacologica Sinica, 2015, 36(5): 597-605.
[12] Wu W K K, Zhang L, Chan M T V. Autophagy, NAFLD and NAFLD-related HCC [G]//Yu J. Obesity, fatty liver and liver cancer. Singapore: Springer Singapore, 2018: 127-138.
[13] Collins Q F, Liu H Y, Pi J, et al.Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5′-AMP-activated protein kinase[J]. Journal of Biological Chemistry, 2007, 282(41): 30143-30149.
[14] Lin L, Zeng L, Liu A, et al.Role of epigallocatechin gallate in glucose, lipid, and protein metabolism and L-theanine in the metabolism-regulatory effects of epigallocatechin gallate[J]. Nutrients, 2021, 13(11): 4120. doi: 10.3390/nu13114120.
[15] Luo P, Wang F, Wong N K, et al.Divergent roles of Kupffer cell TLR2/3 signaling in alcoholic liver disease and the protective role of EGCG[J]. Cellular and Molecular Gastroenterology and Hepatology, 2020, 9(1): 145-160.
[16] 侯慧敏. 表没食子儿茶素没食子酸酯对非酒精性脂肪性肝病中二肽基肽酶-4活性及表达的影响[D]. 沈阳: 中国医科大学, 2020.
Hou H M.Effect of epigallocatechin gallate on the activity and expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease [D]. Shenyang: China Medical University, 2020.
[17] Chen C, Liu Q, Liu L, et al.Potential biological effects of (-)-epigallocatechin-3-gallate on the treatment of nonalcoholic fatty liver disease[J]. Molecular Nutrition & Food Research, 2018, 62(1): 1700483. doi: 10.1002/mnfr.201700483.
[18] Steinmann J, Buer J, Pietschmann T, et al.Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea[J]. British Journal of Pharmacology, 2013, 168(5): 1059-1073.
[19] Ma Y, Lee G, Heo S Y, et al.Oxidative stress is a key modulator in the development of nonalcoholic fatty liver disease[J]. Antioxidants, 2022, 11(1): 91. doi: 10.3390/antiox11010091.
[20] Li Y Y, Yu Y, Yang L, et al.Insights into the role of oxidative stress in hepatocellular carcinoma development[J]. Frontiers in Bioscience-Landmark, 2023, 28(11): 286. doi: 10.31083/j.fbl2811286.
[21] Todisco S, Santarsiero A, Convertini P, et al.PPARα as a metabolic modulator of the liver: role in the pathogenesis of nonalcoholic steatohepatitis (NASH)[J]. Biology, 2022, 11(5): 792. doi: 10.3390/biology11050792.
[22] Montagner A, Polizzi A, Fouché E, et al.Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD[J]. Gut, 2016, 65(7): 1202-1214.
[23] Wang S, Lin Y K, Gao L, et al.PPAR-γ integrates obesity and adipocyte clock through epigenetic regulation of Bmal1[J]. Theranostics, 2022, 12(4): 1589-1606.
[24] Gawrieh S, Noureddin M, Loo N, et al.Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial[J]. Hepatology, 2021, 74(4): 1809-1824.
[25] Gastaldelli A, Sabatini S, Carli F, et al.PPAR-γ-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH[J]. Liver International, 2021, 41(11): 2659-2670.
[26] Li X Y, Ji P X, Ni X X, et al.Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease[J]. World Journal of Hepatology, 2022, 14(7): 1365-1381.
[27] Saffari Y, Sadrzadeh S M H. Green tea metabolite EGCG protects membranes against oxidative damage in vitro[J]. Life Sciences, 2004, 74(12): 1513-1518.
[28] 林勇, 刘仲华, 严煜钧. 茶叶中EGCG干预大鼠非酒精性脂肪肝的作用及机理研究[C]//中国科学技术协会, 云南省人民政府. 第十六届中国科协年会——分12茶学青年科学家论坛. 昆明: [出版者不详], 2014: 163-169.
Lin Y, Liu Z H, Yan Y J.Study on the effect and mechanism of EGCG in tea in intervening non-alcoholic fatty liver in rats [C]//China Association for Science and Technology, Yunnan Provincial People's Government. The 16th Annual Conference of the Chinese Association for Science and Technology: 12 Tea Science Youth Scientists Forum. Kunming: [s.n.], 2014: 163-169.
[29] 沈晶, 舒恒, 石孟琼, 等. 表没食子儿茶素没食子酸酯对小鼠非酒精性脂肪肝的干预作用[J]. 现代食品科技, 2021, 37(4): 33-43, 71.
Shen J, Shu H, Shi M Q, et al.Effects of epigallocatechin-3-gallate on nonalcoholic fatty liver disease in mice[J]. Modern Food Science and Technology, 2021, 37(4): 33-43, 71.
[30] Kuzu N, Bahcecioglu I H, Dagli A F, et al.Epigallocatechin gallate attenuates experimental non-alcoholic steatohepatitis induced by high fat diet[J]. Journal of Gastroenterology and Hepatology, 2008, 23(8pt2): e465-e470.
[31] 严煜钧, 刘仲华, 林勇, 等. 茶叶中EGCG对非酒精性脂肪肝大鼠的调脂保肝作用研究[J]. 茶叶科学, 2014, 34(3): 221-229.
Yan Y J, Liu Z H, Lin Y, et al.Effects of EGCG from tea on regulating lipid metabolism and alleviating liver injury in rats with non-alcoholic fatty liver disease[J]. Journal of Tea Science, 2014, 34(3): 221-229.
[32] Hussain T, Tan B, Yin Y, et al.Oxidative stress and inflammation: what polyphenols can do for us?[J]. Oxidative Medicine and Cellular Longevity, 2016, 2016: 7432797. doi: 10.1155/2016/7432797.
[33] Bondia-Pons I, Ryan L, Martinez J A.Oxidative stress and inflammation interactions in human obesity[J]. Journal of Physiology and Biochemistry, 2012, 68(4): 701-711.
[34] Hulsmans M, Holvoet P.The vicious circle between oxidative stress and inflammation in atherosclerosis[J]. Journal of Cellular and Molecular Medicine, 2010, 14(1/2): 70-78.
[35] Mancini A, Di Segni C, Raimondo S, et al.Thyroid hormones, oxidative stress, and inflammation[J]. Mediators of Inflammation, 2016, 2016: 6757154. doi: 10.1155/2016/6757154.
[36] Hou H M, Yang W L, Bao S Q, et al.Epigallocatechin gallate suppresses inflammatory responses by inhibiting toll-like receptor 4 signaling and alleviates insulin resistance in the livers of high-fat-diet rats[J]. Journal of Oleo Science, 2020, 69(5): 479-486.
[37] Xiao J, Ho C T, Liong E C, et al.Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways[J]. European Journal of Nutrition, 2014, 53(1): 187-199.
[38] Ding Y, Sun X, Chen Y, et al.Epigallocatechin gallate attenuated non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet[J]. European Journal of Pharmacology, 2015, 761: 405-412.
[39] Kochi T, Shimizu M, Terakura D, et al.Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions[J]. Cancer Letters, 2014, 342(1): 60-69.
[40] Itoh N, Nakayama Y, Konishi M.Roles of FGFs as paracrine or endocrine signals in liver development, health, and disease[J]. Frontiers in Cell and Developmental Biology, 2016, 4: 30. doi: 10.3389/fcell.2016.00030.
[41] Hosseini S P, Farivar S, Rezaei R, et al.Fibroblast growth factor 2 reduces endoplasmic reticulum stress and apoptosis in in-vitro non-alcoholic fatty liver disease model[J]. DARU Journal of Pharmaceutical Sciences, 2023, 31(1): 29-37.
[42] Herzig S, Shaw R J.AMPK: guardian of metabolism and mitochondrial homeostasis[J]. Nature Reviews Molecular Cell Biology, 2018, 19(2): 121-135.
[43] Ruderman N B, Carling D, Prentki M, et al.AMPK, insulin resistance, and the metabolic syndrome[J]. The Journal of Clinical Investigation, 2013, 123(7): 2764-2772.
[44] Chen F F, Zhan J Y, Liu M, et al.FGF2 alleviates microvascular ischemia-reperfusion injury by KLF2-mediated ferroptosis inhibition and antioxidant responses[J]. International Journal of Biological Sciences, 2023, 19(13): 4340-4359.
[45] Zhang Y Y, Yin R L, Lang J N, et al.Epigallocatechin-3-gallate ameliorates hepatic damages by relieve FGF21 resistance and promotion of FGF21-AMPK pathway in mice fed a high fat diet[J]. Diabetology & Metabolic Syndrome, 2022, 14(1): 53. doi: 10.1186/s13098-022-00823-y.
[46] Zhang H, Zhang E X, Hu H B.Role of ferroptosis in non-alcoholic fatty liver disease and its implications for therapeutic strategies[J]. Biomedicines, 2021, 9(11): 1660. doi: 10.3390/biomedicines9111660.
[47] Wu J, Wang Y, Jiang R T, et al.Ferroptosis in liver disease: new insights into disease mechanisms[J]. Cell Death Discovery, 2021, 7(1): 276. doi: 10.1038/s41420-021-00660-4.
[48] Yu Y, Yan Y, Niu F L, et al.Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases[J]. Cell Death Discovery, 2021, 7(1): 193. doi: 10.1038/s41420-021-00579-w.
[49] Chen Y, Fang Z M, Yi X, et al.The interaction between ferroptosis and inflammatory signaling pathways[J]. Cell Death & Disease, 2023, 14(3): 205. doi: 10.1038/s41419-023-05716-0.
[50] Ding S B, Chu X L, Jin Y X, et al.Epigallocatechin gallate alleviates high-fat diet-induced hepatic lipotoxicity by targeting mitochondrial ROS-mediated ferroptosis[J]. Frontiers in Pharmacology, 2023, 14: 1148814. doi: 10.3389/fphar.2023.1148814.
[51] Yang C J, Wu A M, Tan L Q, et al.Epigallocatechin-3-gallate alleviates liver oxidative damage caused by iron overload in mice through inhibiting ferroptosis[J]. Nutrients, 2023, 15(8): 1993. doi: 10.3390/nu15081993.
[52] Gan L, Meng Z J, Xiong R B, et al.Green tea polyphenol epigallocatechin-3-gallate ameliorates insulin resistance in non-alcoholic fatty liver disease mice[J]. Acta Pharmacologica Sinica, 2015, 36(5): 597-605.
[53] Alavinejad S P, Eshkiki Z S, Pourmousa Z, et al.A pilot study of epigallocatechin gallate treatment in patients with non-alcoholic fatty liver[J]. Govaresh, 2020, 25(2): 141-148.
[54] Liu H W, Chan Y C, Wang M F, et al.Dietary (-)-epigallocatechin-3-gallate supplementation counteracts aging-associated skeletal muscle insulin resistance and fatty liver in senescence-accelerated mouse[J]. Journal of Agricultural and Food Chemistry, 2015, 63(38): 8407-8417.
[55] 黄超群, 骆曜骏, 王新霞. 表没食子儿茶素没食子酸酯对脂质代谢的调控机制及其在畜禽生产中的应用[J]. 动物营养学报, 2023, 35(1): 86-98.
Huang C Q, Luo Y J, Wang X X.Regulation mechanism of epigallocatechin gallate on lipid metabolism and its application in livestock and poultry production[J]. Chinese Journal of Animal Nutrition, 2023, 35(1): 86-98.
[56] 宋莹莹, 张聪, 屈雅琴, 等. 表没食子儿茶素没食子酸酯激活SIRT6/AMPK信号通路改善果糖饮食诱导小鼠非酒精性脂肪性肝病的作用研究[J]. 中药新药与临床药理, 2023, 34(2): 184-191.
Song Y Y, Zhang C, Qu Y Q, et al.EGCG attenuates fructose-fed induced NAFLD in mice via activating SIRT6/AMPK signaling[J]. Traditional Chinese Drug Research and Clinical Pharmacology, 2023, 34(2): 184-191.
[57] Lerrer B, Gertler A A, Cohen H Y.The complex role of SIRT6 in carcinogenesis[J]. Carcinogenesis, 2016, 37(2): 108-118.
[58] Tasselli L, Zheng W, Chua K F.SIRT6: novel mechanisms and links to aging and disease[J]. Trends in Endocrinology & Metabolism, 2017, 28(3): 168-185.
[59] Pan H Z, Guan D, Liu X M, et al.SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2[J]. Cell Research, 2016, 26(2): 190-205.
[60] Lu J, Fang B C, Huang Y X, et al.Epigallocatechin-3-gallate protects against 1,3-dichloro-2-propanol-induced lipid accumulation in C57BL/6J mice[J]. Life Sciences, 2018, 209: 324-331.
[61] Ueno T, Torimura T, Nakamura T, et al.Epigallocatechin-3-gallate improves nonalcoholic steatohepatitis model mice expressing nuclear sterol regulatory element binding protein-1c in adipose tissue[J]. International Journal of Molecular Medicine, 2009, 24(1): 17-22.
[62] González-Rodríguez Á, Mayoral R, Agra N, et al.Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD[J]. Cell Death & Disease, 2014, 5(4): e1179. doi: 10.1038/cddis.2014.162.
[63] Mao Y Q, Yu F J, Wang J B, et al.Autophagy: a new target for nonalcoholic fatty liver disease therapy[J]. Hepatic Medicine: Evidence and Research, 2016, 8: 27-37.
[64] Chu Q, Zhang S, Chen M, et al.Cherry anthocyanins regulate NAFLD by promoting autophagy pathway[J]. Oxidative Medicine and Cellular Longevity, 2019, 2019: 4825949. doi: 10.1155/2019/4825949.
[65] Zhou J, Farah B L, Sinha R A, et al.Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance[J]. Plos One, 2014, 9(1): e87161. doi: 10.1371/journal.pone.0087161.
[66] Jia Q, Yang R, Mehmood S, et al.Epigallocatechin-3-gallate attenuates myocardial fibrosis in diabetic rats by activating autophagy[J]. Experimental Biology and Medicine, 2022, 247(17): 1591-1600.
[67] Wu D D, Liu Z G, Wang Y Z, et al.Epigallocatechin-3-gallate alleviates high-fat diet-induced nonalcoholic fatty liver disease via inhibition of apoptosis and promotion of autophagy through the ROS/MAPK signaling pathway[J]. Oxidative Medicine and Cellular Longevity, 2021, 2021: 5599997. doi: 10.1155/2021/5599997.
[68] Shang L B, Wang X D.AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation[J]. Autophagy, 2011, 7(8): 924-926.
[69] Holczer M, Besze B, Zámbó V, et al.Epigallocatechin-3-gallate (EGCG) promotes autophagy-dependent survival via influencing the balance of mTOR-AMPK pathways upon endoplasmic reticulum stress[J]. Oxidative Medicine and Cellular Longevity, 2018, 2018: 6721530. doi: 10.1155/2018/6721530.
[70] Leung C, Rivera L, Furness J B, et al.The role of the gut microbiota in NAFLD[J]. Nature Reviews Gastroenterology & Hepatology, 2016, 13(7): 412-425.
[71] Gan R Y, Li H B, Sui Z Q, et al.Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): an updated review[J]. Critical Reviews in Food Science and Nutrition, 2018, 58(6): 924-941.
[72] 左高隆. 茶叶EGCG通过肠-肝轴途径改善非酒精性脂肪肝的作用及机制[D]. 长沙: 湖南农业大学, 2020.
Zuo G L.Effects and mechanisms of EGCG from tea on alleivating nonalcoholic fatty liver through gut liver axis pathway [D]. Changsha: Hunan Agricultural University, 2020
[73] Shi M, Watson E, Conlon M, et al.Impact of co-delivery of EGCG and tuna oil within a broccoli matrix on human gut microbiota, phenolic metabolites and short chain fatty acids in vitro[J]. Molecules, 2022, 27(3): 656. doi: 10.3390/molecules27030656.
[74] Liu X X, Zhao K, Jing N N, et al.Epigallocatechin gallate (EGCG) promotes the immune function of ileum in high fat diet fed mice by regulating gut microbiome profiling and immunoglobulin production[J]. Frontiers in Nutrition, 2021, 8: 720439. doi: 10.3389/fnut.2021.720439.
[75] Huang J B, Li W J, Liao W J, et al.Green tea polyphenol epigallocatechin-3-gallate alleviates nonalcoholic fatty liver disease and ameliorates intestinal immunity in mice fed a high-fat diet[J]. Food & Function, 2020, 11(11): 9924-9935.
[76] Ning K T, Lu K K, Chen Q, et al.Epigallocatechin gallate protects mice against methionine-choline-deficient-diet-induced nonalcoholic steatohepatitis by improving gut microbiota to attenuate hepatic injury and regulate metabolism[J]. ACS Omega, 2020, 5(33): 20800-20809.
[77] Zhou J H, Ding L J, Chen W, et al.Green tea catechin epigallocatechin gallate alleviates high-fat diet-induced obesity in mice by regulating the gut-brain axis[J]. Food Frontiers, 2023, 4(3): 1413-1425.
[78] Lin C Z, Yu B Q, Chen L X, et al.Obeticholic acid induces hepatoxicity via fxr in the NAFLD mice[J]. Frontiers in Pharmacology, 2022, 13: 880508. doi: 10.3389/fphar.2022.880508.
[79] Gottlieb A, Canbay A.Why bile acids are so important in non-alcoholic fatty liver disease (NAFLD) progression[J]. Cells, 2019, 8(11): 1358. doi: 10.3390/cells8111358.
[80] Guo J Y, Huang S Y, Yi Q C, et al.Hepatic Clstn3 ameliorates lipid metabolism disorders in high fat diet-induced NAFLD through activation of FXR[J]. ACS Omega, 2023, 8(29): 26158-26169.
[81] Carr R M, Reid A E.FXR agonists as therapeutic agents for non-alcoholic fatty liver disease[J]. Current Atherosclerosis Reports, 2015, 17(4): 16. doi: 10.1007/s11883-015-0500-2.
[82] Yang Z X, Shen W, Sun H.Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease[J]. Hepatology International, 2010, 4(4): 741-748.
[83] Jiao N, Baker S S, Chapa-Rodriguez A, et al.Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[J]. Gut, 2018, 67(10): 1881-1891.
[84] Sheng L, Jena P K, Liu H X, et al.Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila[J]. The FASEB Journal, 2018, 32(12): 6371-6384.
[85] Huang J B, Feng S M, Liu A N, et al.Green tea polyphenol EGCG alleviates metabolic abnormality and fatty liver by decreasing bile acid and lipid absorption in mice[J]. Molecular Nutrition & Food Research, 2018, 62(4): 1700696. doi: 10.1002/mnfr.201700696.
[86] Rasheed N O A, Ahmed L A, Abdallah D M, et al. Nephro-toxic effects of intraperitoneally injected EGCG in diabetic mice: involvement of oxidative stress, inflammation and apoptosis[J]. Scientific Reports, 2017, 7(1): 40617. doi: 10.1038/srep40617.
[87] Hu J, Webster D, Cao J, et al.The safety of green tea and green tea extract consumption in adults: results of a systematic review[J]. Regulatory Toxicology and Pharmacology, 2018, 95: 412-433.
[88] Wang D X, Wang Y J, Wan X C, et al.Green tea polyphenol (-)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: responses of major antioxidant enzymes and the Nrf2 rescue pathway[J]. Toxicology and Applied Pharmacology, 2015, 283(1): 65-74.
[89] Lambert J D, Kennett M J, Sang S, et al.Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice[J]. Food and Chemical Toxicology, 2010, 48(1): 409-416.
[90] Hirsch N, Konstantinov A, Anavi S, et al.Prolonged feeding with green tea polyphenols exacerbates cholesterol-induced fatty liver disease in mice[J]. Molecular Nutrition & Food Research, 2016, 60(12): 2542-2553.
[91] Dekant W, Fujii K, Shibata E, et al.Safety assessment of green tea based beverages and dried green tea extracts as nutritional supplements[J]. Toxicology Letters, 2017, 277: 104-108.
[92] Ouyang J, Zhu K, Liu Z H, et al.Prooxidant effects of epigallocatechin-3-gallate in health benefits and potential adverse effect[J]. Oxidative Medicine and Cellular Longevity, 2020, 2020: 9723686. doi: 10.1155/2020/9723686.