杜田田,安纪红

非酒精性脂肪性肝病（NAFLD）是全球最普遍的肝病，影响20-25%的成年人口。在25%的患者中，NAFLD进展为非酒精性脂肪性肝炎（NASH），这增加了肝硬化，肝衰竭和肝细胞癌发展的风险。在NASH患者中，肝纤维化是死亡率的主要决定因素。早期的肝纤维化经过规范有效的抗肝纤治疗后可以逆转，若不及时给予干预，肝纤维化的程度将逐渐加重并进展为肝硬化，最终发展为肝细胞癌。因此，积极防治肝纤维化具有重要意义。然而目前西医对于肝纤维化的治疗比较单一、局限，缺乏疗效确切且公认的抗纤维化药物，现有的治疗手段无法满足医疗需求。随着国内外学者的研究深入，中草药成为了逆转肝纤维化和抗纤维化进展的热点，并发现了多层次、多靶点、多途径的优势。

非酒精性脂肪性肝炎；肝纤维化；中药；作用机制

[1] V. Ajmera, P. Belt, L.A. Wilson, R.M. Gill, R. Loomba, D.E. Kleiner, B. A. Neuschwander-Tetri, N. Terrault, N. Nonalcoholic Steatohepatitis Clinical Research, Am1ong patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis, Clin. Gastroenterol. Hepatol. 16 (9) (2018) 1511–1520, e5. [2] D.J. van der Windt, V. Sud, H. Zhang, A. Tsung, H. Huang, The effects of physical exercise on fatty liver disease, Gene Expr. 18 (2) (2018) 89–101. [3] S. Ikramuddin, J. Korner, W.J. Lee, A.J. Thomas, J.E. Connett, J.P. Bantle, D. B. Leslie, Q. Wang, W.B. Inabnet, R.W. Jeffery, K. Chong, L.M. Chuang, M. D. Jensen, A. Vella, L. Ahmed, K. Belani, C.J. Billington, Lifestyle intervention and medical management with vs without Roux-en-Y gastric bypass and control of hemoglobin A1c, LDL cholesterol, and systolic blood pressure at 5 years in the diabetes surgery study, JAMA 319 (3) (2018) 266–278. [4] I. Mikolasevic, T. Filipec-Kanizaj, M. Mijic, I. Jakopcic, S. Milic, I. Hrstic, N. Sobocan, D. Stimac, P. Burra, Nonalcoholic fatty liver disease and liver transplantation – where do we stand? World J. Gastroenterol. 24 (14) (2018) 1491–1506. [5] M. Romero-G´omez, S. Zelber-Sagi, M. Trenell, Treatment of NAFLD with diet, physical activity and exercise, J. Hepatol. 67 (4) (2017) 829–846. [6] N. Alkhouri, A. Scott, An update on the pharmacological treatment of nonalcoholic fatty liver disease: beyond lifestyle modifications, Clin. Liver Dis. 11 (4) (2018) 82–86. [7] R. Vuppalanchi, M. Noureddin, N. Alkhouri, A.J. Sanyal, Therapeutic pipeline in nonalcoholic steatohepatitis, Nat. Rev. Gastroenterol. Hepatol. 18 (6) (2021) 373–392. [8] X. Zheng, M.G. Zhao, C.H. Jiang, X.P. Sheng, H.M. Yang, Y. Liu, X.M. Yao, J. Zhang, Z.Q. Yin, Triterpenic acids-enriched fraction from Cyclocarya paliurus attenuates insulin resistance and hepatic steatosis via PI3K/Akt/GSK3β pathway, Phytomedicine 66 (2020), 153130. [9] Y. Liu, W. Xu, T. Zhai, J. You, Y. Chen, Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway, Acta Pharm. Sin. B 9 (4) (2019) 745–757. [10] J. Zhang, H. Zhang, X. Deng, N. Zhang, B. Liu, S. Xin, G. Li, K. Xu, Baicalin attenuates non-alcoholic steatohepatitis by suppressing key regulators of lipid metabolism, inflammation and fibrosis in mice, Life Sci. 192 (2018) 46–54. [11] D. Yan, Y.Y. Wei, X.M. Li, X.C. Sun, Z. Wang, H.A. Aisa, PFP alleviates nonalcoholic steatohepatitis fatty liver in both Apo E(-/-) mice and Changliver cell[S], Am. J. Transl. Res. 9 (6) (2017) 3073–3083. [12] S.H. Ahn, K.P. Lee, K. Kim, J.Y. Choi, S.Y. Park, J.H. Cheon, Dansameum regulates hepatic lipogenesis and inflammation in vitro and in vivo, Food Sci. Biotechnol. 28 (5) (2019) 1543–1551. [13] T.H. Xie, J.X. Li, T.Y. Mao, Y. Guo, C. Chen, Y.F. Han, X. Tan, R.H. Chen, An ErChen and YinChen decoction ameliorates high-fat-induced nonalcoholic steatohepatitis in rats by regulating JNK1 Signaling pathway, Evid. Based Complement Altern. Med. 2017 (2017), 4603701. [14] N. Xu, X. Wu, H.J. Luo, F.F. Xu, Q.H. Huang, J.Z. Wu, Y.X. Gan, M.Y. Li, Z.Q. Lai, H.R. Lin, J.N. Chen, Z.R. Su, W.P. Ai, Y.H. Liu, Patchouli oil attenuates high fat diet-induced non-alcoholic hepatic steatosis, Planta Med. 86 (4) (2020) 255–266. [15] C. Ho, Y. Gao, D. Zheng, Y. Liu, S. Shan, B. Fang, Y. Zhao, D. Song, Y. Zhang, Q. Li, Alisol A attenuates high-fat-diet-induced obesity and metabolic disorders via the AMPK/ACC/SREBP-1c pathway, J. Cell Mol. Med. 23 (8) (2019) 5108–5118. [16] C. Wu, M. Jing, L. Yang, L. Jin, Y. Ding, J. Lu, Q. Cao, Y. Jiang, Alisol A 24-acetate ameliorates nonalcoholic steatohepatitis by inhibiting oxidative stress and stimulating autophagy through the AMPK/mTOR pathway, Chem. Biol. Inter. 291 (2018) 111–119. [17] J. Liu, R. Sun, Protective effect of Xiaochaihu Decoction on non-alcoholic steatohepatitis model mice, Chin. Tradit. Herb. Drugs 51 (14) (2020) 3708–3716. [18] S. Gao, T. Wang, X. Huang, Y. Jin, Y. Xu, Y. Xi, J. Zhang, Y. Luo, H. Xu, H. Guo, D. Ke, J. Wang, Exploring the protective effect of Modified Xiaochaihu Decoction against hepatic steatosis and inflammation by network pharmacology and validation in ageing rats, Chin. Med. 15 (2020) 96. [19] X.W. Gong, Y.J. Xu, Q.H. Yang, Y.J. Liang, Y.P. Zhang, G.L. Wang, Y.Y. Li, Effect of soothing Gan (Liver) and invigorating Pi (Spleen) recipes on TLR4-p38 MAPK pathway in kupffer cells of non-alcoholic steatohepatitis rats, Chin. J. Integr. Med. 25 (3) (2019) 216–224. [20] H.F. Lu, Y.H. Lai, H.C. Huang, I.J. Lee, L.C. Lin, H.K. Liu, H.H. Tien, C. Huang, Ginseng-plus-Bai-Hu-Tang ameliorates diet-induced obesity, hepatic steatosis, and insulin resistance in mice, J. Ginseng Res. 44 (2) (2020) 238–246. [21] M.T. Liu, Y.J. Huang, T.Y. Zhang, L.B. Tan, X.F. Lu, J. Qin, Lingguizhugan decoction attenuates diet-induced obesity and hepatosteatosis via gut microbiota, World J. Gastroenterol. 25 (27) (2019) 3590–3606. [22] H. Xu, G.F. Chen, Y.S. Ma, H.W. Zhang, Y. Zhou, G.H. Liu, D.Y. Chen, J. Ping, Y. H. Liu, X. Mou, D. Fu, Hepatic proteomic changes and Sirt1/AMPK signaling activation by oxymatrine treatment in rats with non-alcoholic steatosis, Front. Pharmacol. 11 (2020) 216. [23] Y. Yao, Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet‑induced obese mice via endoplasmic reticulum stress and p‑STAT3/ STAT3 signaling, Mol. Med. Rep. 21 (3) (2020) 1059–1070. [24] T. Zhai, W. Xu, Y. Liu, K. Qian, Y. Xiong, Y. Chen, Honokiol alleviates methionine- choline deficient diet-induced hepatic steatosis and oxidative stress in C57BL/6 mice by regulating CFLAR-JNK pathway, Oxid. Med. Cell Longev. 2020 (2020), 2313641. [25] T. Lan, Y. Yu, J. Zhang, H. Li, Q. Weng, S. Jiang, S. Tian, T. Xu, S. Hu, G. Yang, Y. Zhang, W. Wang, L. Wang, Q. Zhu, X. Rong, J. Guo, Cordycepin ameliorates nonalcoholic steatohepatitis via activation of AMP-activated protein kinase signaling pathway, Hepatology (2021). [26] X. Tian, Q. Ru, Q. Xiong, R. Wen, Y. Chen, Catalpol attenuates hepatic steatosis by regulating lipid metabolism via AMP-activated protein kinase activation, Biomed. Res. Int. 2020 (2020), 6708061. [27] H.U. Fei-Fei, H. Zhan-Xia, Z. Shao-Bo, S. Yu-Chen, J.I. Li-Li, Study on improvement provided by water extracts of Polygoni Multiflori Radix and Polygoni Multiflori Radix Praeparata on non-alcoholic steatohepatitis in mice induced by MCD, Zhongguo Zhong Yao Za Zhi 45 (19) (2020) 4732–4739. [28] Q. Meng, X.P. Duan, C.Y. Wang, Z.H. Liu, P.Y. Sun, X.K. Huo, H.J. Sun, J.Y. Peng, K.X. Liu, Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation, Acta Pharmacol. Sin. 38 (1) (2017) 69–79. [29] C.H. Zhang, Q. Xiao, J.Q. Sheng, T.T. Liu, Y.Q. Cao, Y.N. Xue, M. Shi, Z. Cao, L. F. Zhou, X.Q. Luo, K.Z. Deng, C. Chen, Gegen qinlian decoction abates nonalcoholic steatohepatitis associated liver injuries via anti-oxidative stress and anti-inflammatory response involved inhibition of toll-like receptor 4 signaling pathways, Biomed. Pharmacother. 126 (2020), 110076. [30] Y. Zhang, X. Zhu, D. Zheng, Y. Yin, M. Peng, J. Wang, Effects of Qutan Huoxue formula on the SOCS1/TLR4 signaling pathway in NASH model mice, Evid. Based Complement Altern. Med. 2020 (2020), 1570918. [31] J. Xiao, F. Wang, E.C. Liong, K.F. So, G.L. Tipoe, Lycium barbarum polysaccharides improve hepatic injury through NFkappa-B and NLRP3/6 pathways in a methionine choline deficient diet steatohepatitis mouse model, Int. J. Biol. Macromol. 120 (Pt B) (2018) 1480–1489. [32] H. Jeong, J.W. Kim, M.S. Yang, C. Park, J.H. Kim, C.W. Lim, B. Kim, Beneficial effects of Korean red ginseng in the progression of non-alcoholic steatohepatitis via FABP4 modulation, Am. J. Chin. Med. (2018) 1–27. [33] I.C. Yen, J.C. Lin, Y. Chen, Q.W. Tu, S.Y. Lee, Antrodia Cinnamomea attenuates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation in vitro and in vivo, Am. J. Chin. Med. 48 (8) (2020) 1859–1874. [34] Y. Ma, T. Han, S. Yang, C. Yu, X. Shi, Y. Wu, Efficacy of Cigu Xiaozhi pill on non- alcoholic steatohepatitis-associated lipoapoptosis through stress-activated c-Jun N-terminal kinase signalling pathway, J. Tradit. Chin. Med. 41 (1) (2021) 79–88. [35] X. Shu, M. Wang, H. Xu, Y. Liu, J. Huang, Z. Yao, L. Zhang, Extracts of Salvia- Nelumbinis naturalis ameliorate nonalcoholic steatohepatitis via inhibiting gut- derived endotoxin mediated TLR4/NF-κB activation, Evid. Based Complement Altern. Med. 2017 (2017), 9208314. [36] L. Xiao, S. Liang, L. Ge, S. Qiu, H. Wan, S. Wu, J. Fei, S. Peng, X. Zeng, Si-Wei- Qing-Gan-Tang improves non-alcoholic steatohepatitis by modulating the nuclear factor-κB signal pathway and autophagy in methionine and choline deficient diet- fed rats, Front. Pharmacol. 11 (2020) 530. [37] A.B. Marcher, S.M. Bendixen, M.K. Terkelsen, S.S. Hohmann, M.H. Hansen, B. D. Larsen, S. Mandrup, H. Dimke, S. Detlefsen, K. Ravnskjaer, Transcriptional regulation of Hepatic Stellate Cell activation in NASH, Sci. Rep. 9 (1) (2019) 2324. [38] I. Milosevic, A. Vujovic, A. Barac, M. Djelic, M. Korac, A. Radovanovic Spurnic, I. Gmizic, O. Stevanovic, V. Djordjevic, N. Lekic, E. Russo, A. Amedei, Gut-liver axis, gut microbiota, and its modulation in the management of liver diseases: a review of the literature, Int. J. Mol. Sci. 20 (2019) 2. [39] Y. Wang, Y.L. Tai, D. Zhao, Y. Zhang, J. Yan, G. Kakiyama, X. Wang, E.C. Gurley, J. Liu, J. Liu, J. Liu, G. Lai, P.B. Hylemon, W.M. Pandak, W. Chen, H. Zhou, Berberine prevents disease progression of nonalcoholic steatohepatitis through modulating multiple pathways, Cells 10 (2021) 2. [40] N. Jia, X. Lin, S. Ma, S. Ge, S. Mu, C. Yang, S. Shi, L. Gao, J. Xu, T. Bo, J. Zhao, Amelioration of hepatic steatosis is associated with modulation of gut microbiota and suppression of hepatic miR-34a in Gynostemma pentaphylla (Thunb.) Makino treated mice, Nutr. Metab. 15 (2018) 86. [41] M.J. Gong, C.Y. Zhu, Z.J. Zou, B. Han, P. Huang, Therapeutic potential of puerarin against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis determined by combination of (1)H NMR spectroscopy-based metabonomics and 16S rRNA gene sequencing, J. Pharm. Biomed. Anal. 197 (2021), 113964. [42] H. Li, Y. Xi, X. Xin, H. Tian, Y. Hu, Salidroside improves high-fat diet-induced non-alcoholic steatohepatitis by regulating the gut microbiota-bile acid-farnesoid X receptor axis, Biomed. Pharmacother. 124 (2020), 109915. [43] Y. Hong, B. Li, N. Zheng, G. Wu, J. Ma, X. Tao, L. Chen, J. Zhong, L. Sheng, H. Li, Integrated metagenomic and metabolomic analyses of the effect of Astragalus Polysaccharides on alleviating high-fat diet-induced metabolic disorders, Front. Pharmacol. 11 (2020) 833. [44] J. Zheng, L. Zhu, B. Hu, X. Zou, H. Hu, Z. Zhang, N. Jiang, J. Ma, H. Yang, H. Liu, 1-Deoxynojirimycin improves high fat diet-induced nonalcoholic steatohepatitis by restoring gut dysbiosis, J. Nutr. Biochem. 71 (2019) 16–26. [45] Y. Guo, P.H. Ding, L.J. Liu, L. Shi, T.Y. Mao, J.X. Li, Y.L. Wang, Gegen qinlian decoction attenuates high-fat diet-induced steatohepatitis in rats via gut microbiota, Evid. Based Complement Altern. Med. 2018 (2018), 7370891. [46] J.E. Lee, S.M. Lee, J. Jung, Integrated omics analysis unraveled the microbiome- mediated effects of Yijin-Tang on hepatosteatosis and insulin resistance in obese mouse, Phytomedicine 79 (2020), 153354. [47] J. Leng, F. Huang, Y. Hai, H. Tian, W. Liu, Y. Fang, Y. Hu, J. Peng, Amelioration of non-alcoholic steatohepatitis by Qushi Huayu decoction is associated with inhibition of the intestinal mitogen-activated protein kinase pathway, Phytomedicine 66 (2020), 153135. [48]J.H. Peng, J. Leng, H.J. Tian, T. Yang, Y. Fang, Q. Feng, Y. Zhao, Y.Y. Hu, Geniposide and chlorogenic acid combination ameliorates non-alcoholic steatohepatitis involving the protection on the gut barrier function in mouse induced by high-fat diet, Front. Pharmacol. 9 (2018) 1399. [49] Q. Li, M. Li, F. Li, W. Zhou, Y. Dang, L. Zhang, G. Ji, Qiang-Gan formula extract improves non-alcoholic steatohepatitis via regulating bile acid metabolism and gut microbiota in mice, J. Ethnopharmacol. 258 (2020), 112896.

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