PDF下载 ( 2076 KB)
虎杖活性成分治疗非酒精性脂肪性肝病的相关信号通路及相互作用
DOI: 10.3969/j.issn.1001-5256.2022.04.033
利益冲突声明：所有作者均声明不存在利益冲突。
作者贡献声明：李淑娣负责课题设计，资料分析; 陈欣菊、刘江凯、王振、段飞负责修改论文; 袁卓雅、梁磊负责归纳总结文献资料; 李素领负责拟定写作思路，指导撰写文章并最后定稿。
Signaling pathways involved in the active components of Polygonum cuspidatum in treatment of nonalcoholic fatty liver disease and their interaction
-
摘要: 非酒精性脂肪性肝病(NAFLD)的发病机制尚不清楚，且目前尚无任何治疗NAFLD的有效药物获批。虎杖是药用历史悠久的天然中药，研究证实其在治疗NAFLD中可发挥重要作用。本文通过梳理近年来虎杖活性成分应用于NAFLD的相关研究成果，可见虎杖活性成分通过调控核因子E2相关因子2、腺苷酸活化蛋白激酶、NF-κB、沉默信息调节因子1和过氧化物酶体增殖物激活受体α等多条相关信号通路，发挥改善胰岛素抵抗、抗氧化应激、调节脂质代谢、改善内质网应激、减轻炎症浸润等作用，达到防治NAFLD的作用，以期为NAFLD治疗药物研发及机制探索提供依据和思路。Abstract: The pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear, and currently no effective drugs have been approved for the treatment of NAFLD. Polygonum cuspidatum is a natural traditional Chinese medicine with a long history of application, and studies have shown that it plays an important role in the treatment of NAFLD. This article summarizes related research findings in the active components of Polygonum cuspidatum applied in the treatment of NAFLD, and it is found that the active components of Polygonum cuspidatum can improve insulin resistance, exert an anti-oxidative stress effect, regulate lipid metabolism, improve endoplasmic reticulum stress, and alleviate inflammatory infiltration by regulating the signaling pathways including Nrf2, AMPK, NF-κB, SIRT1, and PPARα, thereby exerting a preventive and therapeutic effect on NAFLD, so as to provide a basis and ideas for developing drugs for NAFLD and exploring related mechanisms.
-
图 1 虎杖活性成分治疗NAFLD的细胞信号通路机制
Figure 1. Mechanism of cell signaling pathway in treatment of NAFLD by active ingredients of Polygonum cuspidatum
表 1 虎杖活性成分调节Nrf2通路作用于NAFLD的效应路径
Table 1. Active ingredients of Polygonum cuspidatum regulates the effect pathway of Nrf2 pathway on NAFLD
路径 效应指标 抗氧化应激 SOD、GSH、CAT↑; MDA↓ 调节脂质代谢 HO-1、CPT1↑ 减轻炎症反应 TNFα、IL-1β、IL-6↓ 注：↑上调; ↓下调。 
下载: 导出CSV
表 2 虎杖活性成分调节AMPK通路作用于NAFLD的效应路径
Table 2. Active ingredients of Polygonum cuspidatum regulates the pathway of AMPK pathway on NAFLD
路径 效应指标 调节脂质代谢 PPARα、SREBP-1c、ChREBP↑; FASN、SCD1↓ 改善胰岛素抵抗 脂联素↑ 减轻炎症反应 SREBP-1c↓ 注：↑上调; ↓下调。FASN，脂肪酸合酶; SCD1，硬脂酰辅酶A去饱合酶1。
下载: 导出CSV
表 3 虎杖活性成分调节NF-κB通路作用于NAFLD的效应路径
Table 3. Active ingredients of Polygonum cuspidatum regulates the pathway of NF-κB pathway on NAFLD
路径 效应指标 减轻炎症反应 TNFα、IL-1β、IL-6↓ 改善胰岛素抵抗 ERK、IL-6、TNFα、LPS↓ 注：↓下调。
下载: 导出CSV
表 4 虎杖活性成分调节SIRT1通路作用于NAFLD的效应路径
Table 4. Active ingredients of Polygonum cuspidatum regulates the pathway of SIRT1 pathway on NAFLD
路径 效应指标 调节脂质代谢 ATF6、LC3↓; GLUT4↑ 改善内质网应激 ERK、IL-6、TNFα、LPS↓ 注：↑上调; ↓下调。
下载: 导出CSV
表 5 虎杖活性成分调节PPARα通路作用于NAFLD的效应路径
Table 5. Active ingredients of Polygonum cuspidatum regulates the pathway of PPARα pathway on NAFLD
路径 效应指标 调节脂质代谢 FASN、SCD1↓; PPARα、CPT1↑ 改善氧化应激 PKA、AMPK↑ 注：↑上调; ↓下调。
下载: 导出CSV
-
[1] ESLAM M, SARIN SK, WONG VW, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease[J]. Hepatol Int, 2020, 14(6): 889-919. DOI: 10.1007/s12072-020-10094-2. [2] 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]. J Hepatol, 2019, 71(4): 793-801. DOI: 10.1016/j.jhep.2019.06.021. [3] ZHOU Q, SU J, JI MY. Progress in the treatment of nonalcoholic fatty liver disease[J]. China Med Herald, 2020, 17(6): 26-29. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202006008.htm周谦, 苏娟, 季梦遥. 非酒精性脂肪性肝病的治疗研究进展[J]. 中国医药导报, 2020, 17(6): 26-29. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202006008.htm [4] GOLABI P, SAYINER M, FAZEL Y, et al. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis[J]. Expert Rev Gastroenterol Hepatol, 2016, 10(1): 63-71. DOI: 10.1586/17474124.2016.1099433. [5] ZHANG YT, HUANG X, CHEN YZ, et al. Chemical constituents and their biosynthesis mechanisms of Polygonum cuspidatum[J]. China J Chin Mater Med, 2020, 45(18): 4364-4372. DOI: 10.19540/j.cnki.cjcmm.20200525.201.张云婷, 黄晓, 陈运中, 等. 虎杖主要化学成分及其生物合成机制研究进展[J]. 中国中药杂志, 2020, 45(18): 4364-4372. DOI: 10.19540/j.cnki.cjcmm.20200525.201. [6] FAN HT, DING SL, LIN HS. Pharmacological of polygoni cuspidati rhizoma[J]. China J Chin Mater Med, 2013, 38(15): 2545-2548. DOI: 10.3321/j.issn:1001-5302.2000.11.003.樊慧婷, 丁世兰, 林洪生. 中药虎杖的药理研究进展[J]. 中国中药杂志, 2013, 38(15): 2545-2548. DOI: 10.3321/j.issn:1001-5302.2000.11.003. [7] JI QX, XU XL. Effect of polydatin on age- and diet-associated non-alcoholic steatohepatitis in LDL receptor knockout mice and its possible mechanisms[J]. China Tradit Herb Drugs, 2021, 52(12): 3602-3610. DOI: 10.7501/j.issn.0253-2670.2021.12.017.吉秋霞, 许晓乐. 虎杖苷对高脂喂养的中年LDLr-/-小鼠非酒精性脂肪肝炎的作用及机制研究[J]. 中草药, 2021, 52(12): 3602-3610. DOI: 10.7501/j.issn.0253-2670.2021.12.017. [8] XU ZG, ZHANG PH. Attenuation of hepatic ischemia-reperfusion injury by polydatin in rats via Nrf2/HO-1 signaling pathway[J]. Chin Tradit Patmed, 43(2): 362-368. DOI: 10.3969/j.issn.1001-1528.2021.02.012.徐志广, 张朴花. 虎杖苷通过调控Nrf2/HO-1信号通路减轻大鼠肝脏缺血再灌注损伤[J]. 中成药, 43(2): 362-368. DOI: 10.3969/j.issn.1001-1528.2021.02.012. [9] HUBBARD BP, SINCLAIR DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases[J]. Trends Pharmacol Sci, 2014, 35(3): 146-154. DOI: 10.1016/j.tips.2013.12.004. [10] HUANG Y, LANG H, CHEN K, et al. Resveratrol protects against nonalcoholic fatty liver disease by improving lipid metabolism and redox homeostasis via the PPARα pathway[J]. Appl Physiol Nutr Metab, 2020, 45(3): 227-239. DOI: 10.1139/apnm-2019-0057. [11] AHMED SM, LUO L, NAMANI A, et al. Nrf2 signaling pathway: Pivotal roles in inflammation[J]. Biochim Biophys Acta Mol Basis Dis, 2017, 1863(2): 585-597. DOI: 10.1016/j.bbadis.2016.11.005. [12] WANG X, LI C, XU S, et al. NF-E2-related factor 2 deletion facilitates hepatic fatty acids metabolism disorder induced by high-fat diet via regulating related genes in mice[J]. Food Chem Toxicol, 2016, 94: 186-196. DOI: 10.1016/j.fct.2016.06.011. [13] DU J, ZHANG M, LU J, et al. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK[J]. Endocrine, 2016, 53(3): 701-709. DOI: 10.1007/s12020-016-0926-5. [14] SHARMA RS, HARRISON DJ, KISIELEWSKI D, et al. Experimental nonalcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacologic activation of Nrf2 (NF-E2 p45-related factor 2)[J]. Cell Mol Gastroenterol Hepatol, 2018, 5(3): 367-398. DOI: 10.1016/j.jcmgh.2017.11.016. [15] ZENG MD. Oxygen stress in fatty liver disease and its treatment[J]. Int J Digest Dis, 2005, 25(5): 263-266. https://www.cnki.com.cn/Article/CJFDTOTAL-GWXH200505000.htm曾民德. 脂肪性肝病的氧应激及其治疗对策[J]. 国际消化病杂志, 2005, 25(5): 263-266. https://www.cnki.com.cn/Article/CJFDTOTAL-GWXH200505000.htm [16] NANTHIRUDJANAR T, FURUMOTO H, HIRATA T, et al. Oxidized eicosapentaenoic acids more potently reduce LXRα-induced cellular triacylglycerol via suppression of SREBP-1c, PGC-1β and GPA than its intact form[J]. Lipids Health Dis, 2013, 12: 73. DOI: 10.1186/1476-511X-12-73. [17] PANCHAL SK, POUDYAL H, BROWN L. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats[J]. J Nutr, 2012, 142(6): 1026-1032. DOI: 10.3945/jn.111.157263. [18] DAI J, MA J, LIAO Y, et al. Polydatin protects H9c2 cells from hypoxia-induced injury via up-regulating long non-coding RNA DGCR5[J]. Braz J Med Biol Res, 2019, 52(12): e8834. DOI: 10.1590/1414-431X20198834. [19] WOODS A, VERTOMMEN D, NEUMANN D, et al. Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPKkinases and study of their roles by site-directed mutagenesis[J]. J Biol Chem, 2003, 278(31): 28434-28442. DOI: 10.1074/jbc.M303946200. [20] DAY EA, FORD RJ, STEINBERG GR. AMPK as a therapeutic target for treating metabolic diseases[J]. Trends Endocrinol Metab, 2017, 28(8): 545-560. DOI: 10.1016/j.tem.2017.05.004. [21] LEE MS, HAN HJ, HAN SY, et al. Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation[J]. Nat Commun, 2018, 9(1): 3404. DOI: 10.1038/s41467-018-05721-4. [22] SMITH BK, MARCINKO K, DESJARDINS EM, et al. Treatment of nonalcoholic fatty liver disease: Role of AMPK[J]. Am J Physiol Endocrinol Metab, 2016, 311(4): E730-E740. DOI: 10.1152/ajpendo.00225.2016. [23] ZHANG S, MAO Y, FAN X. Inhibition of ghrelin o-acyltransferase attenuated lipotoxicity by inducing autophagy via AMPK-mTOR pathway[J]. Drug Des Devel Ther, 2018, 12: 873-885. DOI: 10.2147/DDDT.S158985. [24] TONG GY. Research progress of sterol regulatory element binding protein 1C[J]. Int J Endocrinol Metab, 2002, 22(5): 328-331. DOI: 10.3760/cma.j.issn.1673-4157.2002.05.026.童国玉. 固醇调节元件结合蛋白1c的研究进展[J]. 国际内分泌代谢杂志, 2002, 22(5): 328-331. DOI: 10.3760/cma.j.issn.1673-4157.2002.05.026. [25] ZHANG XP, LI ZF. Advances in anti-tumor therapy targeting the EGFR family of receptor tyrosine kinases[J]. Chin Pharmacol Bull, 2003, 19(8): 15-18. DOI: 10.3321/j.issn:1001-1978.2003.08.004.张喜平, 李宗芳. 大黄素的药理作用研究概况[J]. 中国药理学通报, 2003, 19(8): 15-18. DOI: 10.3321/j.issn:1001-1978.2003.08.004. [26] XU YL, WANG GD, LIU B, et al. Emodin activates AMPK/SREBP-1 pathway to reduce fatty acid-induced steatosis in HepG2 cells[J]. J Chin Physician, 2017, 19(4): 506. DOI: 10.3760/cma.j.issn.1008-1372.2017.04.007.徐轶玲, 王国栋, 刘波, 等. 大黄素激活AMPK/SREBP-1通路减少脂肪酸诱导的HepG2细胞脂肪变性[J]. 中国医师杂志, 2017, 19(4): 506. DOI: 10.3760/cma.j.issn.1008-1372.2017.04.007. [27] HUANG MQ, XU W, CHU KD, et al. Recent advances on Chinese medicine and active ingredients in ameliorating insulin resistance via GLUT4 translocation[J]. J TraditChin Med, 2012, 18(16): 343-346. DOI: 10.13422/j.cnki.syfjx.2012.16.028.黄鸣清, 许文, 褚克丹, 等. 基于GLUT4转位的中药及活性成分改善胰岛素抵抗研究进展[J]. 中国实验方剂学杂志, 2012, 18(16): 343-346. DOI: 10.13422/j.cnki.syfjx.2012.16.028. [28] CAO L, MA J. Role of adiponectin in insulin resistance[J]. J Environ Hyg, 2007, 34(5): 301-304. DOI: 10.3969/j.issn.1002-2600.2007.04.048.曹黎, 马静. 脂联素在胰岛素抵抗中的作用[J]. 环境卫生学杂志, 2007, 34(5): 301-304. DOI: 10.3969/j.issn.1002-2600.2007.04.048. [29] WAN CP, WEI YG, LI XX. Piperine regulates glucose metabolism disorder in HepG2cells of insulin resistance models via targeting upstream target of AMPK signaling pathway[J]. China J Chin Mater Med, 2017, 42(3): 542-547. DOI: 10.19540/j.cnki.cjcmm.20161222.059.万春平, 魏雅改, 李晓雪. 胡椒碱对HepG2细胞胰岛素抵抗模型糖代谢AMPK信号通路上游靶点干预机制的研究[J]. 中国中药杂志, 2017, 42(3): 542-547. DOI: 10.19540/j.cnki.cjcmm.20161222.059. [30] ZHANG X, ZHANG R, LV P, et al. Emodin up-regulates glucose metabolism, decreases lipolysis, and attenuates inflammation in vitro[J]. J Diabetes, 2015, 7(3): 360-368. DOI: 10.1111/1753-0407.12190. [31] ZHANG Q, LENARDO MJ, BALTIMORE D. 30 Years of NF-κB: A blossoming of relevance to human pathobiology[J]. Cell, 2017, 168(1-2): 37-57. DOI: 10.1016/j.cell.2016.12.012. [32] SHIH RH, WANG CY, YANG CM. NF-kappaB signaling pathways in neurological inflammation: A mini review[J]. Front Mol Neurosci, 2015, 8: 77. DOI: 10.3389/fnmol.2015.00077. [33] SUN TT, LI JT, WEI HL, et al. Research advances in the role of the TNF-α/NF-κB signaling pathway in the regulation of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2019, 35(9): 2095-2098. DOI: 10.3969/j.issn.1001-5256.2019.09.047.孙婷婷, 李京涛, 魏海梁, 等. TNFα/NF-κB信号通路调控非酒精性脂肪性肝病的研究现状[J]. 临床肝胆病杂志, 2019, 35(9): 2095-2098. DOI: 10.3969/j.issn.1001-5256.2019.09.047. [34] ZHANG R, ZHU RF, XU J, et al. Molecular mechanisms of emodin in inhibiting insulinresist[J]. Shanghai J Tradit Chin Med, 2010, 44(8): 71-73, 79. DOI: 10.16305/j.1007-1334.2010.08.022.张蓉, 朱榕峰, 徐俊, 等. 大黄素改善脂多糖引起的胰岛素抵抗机制研究[J]. 上海中医药杂志, 2010, 44(8): 71-73, 79. DOI: 10.16305/j.1007-1334.2010.08.022. [35] YAO TX. Effect of emodin on endotoxin-induced liver injury in rats with nonalcoholic fatty liver disease[D]. Changsha: Central South University, 2011.姚婷新. 大黄素对非酒精性脂肪肝大鼠内毒素性肝损伤的影响[D]. 长沙: 中南大学, 2011. [36] YANG HR, LI XB, LAO ZX, et al. Progress on pharmacological action of resveratrol[J]. Chin J Gerontol, 2020, 40(16): 3572-3575. DOI: 10.3969/j.issn.1005-9202.2020.16.064.杨海荣, 李雪斌, 劳贞贤, 等. 白藜芦醇药理作用研究进展[J]. 中国老年学杂志, 2020, 40(16): 3572-3575. DOI: 10.3969/j.issn.1005-9202.2020.16.064. [37] TIAN YL. Resveratrol interferes with the signaling mechanism of inflammatory damage in nonalcoholic fatty liver disease in mice[D]. Changchun: Jilin University, 2017.田月丽. 白藜芦醇干预小鼠非酒精性脂肪性肝病炎性损伤的信号机制[D]. 长春: 吉林大学, 2017. [38] MEI Z, ZHANG X, YI J, et al. Sirtuins in metabolism, DNA repair and cancer[J]. J Exp Clin Cancer Res, 2016, 35(1): 182. DOI: 10.1186/s13046-016-0461-5. [39] YANG S, HE SQ. Role of silent information regulator 1 in development and progression of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2018, 34(3): 649-652. DOI: 10.3969/j.issn.1001-5256.2018.03.047.杨帅, 何松青. 沉默调节蛋白1在非酒精性脂肪性肝病发生发展中的作用[J]. 临床肝胆病杂志, 2018, 34(3): 649-652. DOI: 10.3969/j.issn.1001-5256.2018.03.047. [40] ZHANG ZL, SHEN HY, NI HM, et al. Research progress of SIRT1 in lipid metabolism mechanism of nonalcoholic fatty liver disease[J]. Chin J Integr Tradit West Med Liver Dis, 2020, 30(5): 472-474. DOI: 10.3969/j.issn.1005-0264.2020.05.030.张中乐, 沈红艺, 倪红梅, 等. SIRT1在非酒精性脂肪性肝病脂质代谢机制中的作用研究进展[J]. 中西医结合肝病杂志, 2020, 30(5): 472-474. DOI: 10.3969/j.issn.1005-0264.2020.05.030. [41] ZHOU R. Effect and mechanism of resveratrol on lipid droplet accumulation through SIRT1/ATF6[D]. Chongqing: Army Medical University, 2018.周蕊. 白藜芦醇通过SIRT1/ATF6调节脂滴蓄积的作用及机制研究[D]. 重庆: 陆军军医大学, 2018. [42] ZHAO J, YE LF, ZHANG H, et al. Emodin regulates glucose uptake by activating Sirt1 in 3T3-L1 adipocyt[J]. J Nangjing Univ Tradit Chin Med, 2014, 30(6): 546-549. DOI: 10.14148/j.issn.1672-0482.2014.06.014.赵娟, 叶丽芳, 张颢, 等. 大黄素调节Sirt1表达改善脂肪细胞糖代谢的研究[J]. 南京中医药大学学报, 2014, 30(6): 546-549. DOI: 10.14148/j.issn.1672-0482.2014.06.014. [43] ZHANG L, TU R, WANG Y, et al. Early-life exposure to lead induces cognitive impairment in elder mice targeting SIRT1 phosphorylation and oxidative alterations[J]. Front Physiol, 2017, 8: 446. DOI: 10.3389/fphys.2017.00446. [44] DING S, JIANG J, ZHANG G, et al. Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats[J]. PLoS One, 2017, 12(8): e0183541. DOI: 10.1371/journal.pone.0183541. [45] LEFEBVRE P, CHINETTI G, FRUCHART JC, et al. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis[J]. J Clin Invest, 2006, 116(3): 571-580. DOI: 10.1172/JCI27989. [46] WANG Q, LIU S, ZHAI A, et al. AMPK-mediated regulation of lipid metabolism by phosphorylation[J]. Biol Pharm Bull, 2018, 41(7): 985-993. DOI: 10.1248/bpb.b17-00724. [47] 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. DOI: 10.1136/gutjnl-2015-310798. [48] PETTINELLI P, VIDELA LA. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: An additional reinforcing lipogenic mechanism to SREBP-1c induction[J]. J Clin Endocrinol Metab, 2011, 96(5): 1424-1430. DOI: 10.1210/jc.2010-2129. [49] YU DD, van CITTERS G, LI H, et al. Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease[J]. Bioorg Med Chem, 2021, 41: 116193. DOI: 10.1016/j.bmc.2021.116193. [50] CHEN JM, ZHANG SS, LI L, et al. The study of pathological evaluation and regulating effect on lipid metabolism enzyme SERSP-1c and PPAR-α of polydatin in treatment of non alcoholic fatty liver[J]. Chin Arch Tradit Chin Med, 2015, 33(7): 1701-1706. DOI: 10.13193/j.issn.1673-7717.2015.07.049.陈剑明, 张声生, 李琳, 等. 虎杖苷治疗非酒精性脂肪肝的肝脏病理评价及对脂质代谢酶SERSP-1c和PPAR-α的调节作用[J]. 中华中医药学刊, 2015, 33(7): 1701-1706. DOI: 10.13193/j.issn.1673-7717.2015.07.049. [51] de GREGORIO E, COLELL A, MORALES A, et al. Relevance of SIRT1-NF-κB axis as therapeutic target to ameliorate inflammation in liver disease[J]. Int J Mol Sci, 2020, 21(11): 446. DOI: 10.3390/ijms21113858. [52] LI H. Effects of Nrf2 on lipid metabolism and related gene expression in NAFLD model mice[D]. Harbin: Northeast Agricultural University, 2018.李宏. Nrf2对NAFLD模型小鼠脂质代谢及相关基因表达的影响[D]. 哈尔滨: 东北农业大学, 2018. -
本文二维码
图(1) / 表(5)
计量
- 文章访问数: 502
- HTML全文浏览量: 250
- PDF下载量: 39
- 被引次数: 0
