PDF下载 ( 1365 KB)
黄连温胆汤干预代谢相关脂肪性肝病脂质堆积的作用机制
DOI: 10.12449/JCH260522
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：姚康萌负责设计论文框架，拟定写作思路，起草论文；张馨日负责搜集相关文献；郎轶萱负责论文修改；冷炎负责指导撰写文章并最后定稿。姚康萌和张馨日对本文贡献等同，同为第一作者。
Mechanism of action of Huanglian Wendan decoction in treatment of lipid accumulation in metabolic dysfunction-associated fatty liver disease
-
摘要: 代谢相关脂肪性肝病（MAFLD）的核心特征为肝脏脂质堆积，与脂质代谢紊乱、胰岛素抵抗及炎症反应等因素密切相关，而异常的脂质堆积又可加剧上述因素，从而进一步加重脂质堆积，形成恶性循环。黄连温胆汤在改善MAFLD脂质堆积方面展现出独特优势，但其作用机制较为复杂。本文结合最新文献证据，系统总结黄连温胆汤从调节脂质代谢、改善胰岛素抵抗和抗炎等3个方面改善脂质堆积的作用机制以及相关中药活性成分的药理作用，为黄连温胆汤治疗MAFLD的临床应用提供理论依据。Abstract: Metabolic dysfunction-associated fatty liver disease （MAFLD） has the core pathological feature of liver lipid accumulation， which is closely associated with the factors such as lipid metabolism disorders， insulin resistance， and inflammation， and abnormal lipid accumulation can exacerbate these factors and further intensify lipid accumulation， thereby forming a vicious circle. Huanglian Wendan decoction has shown unique advantages in alleviating lipid accumulation associated with MAFLD， but its mechanism of action is relatively complex. With reference to the latest literature evidence， this article systematically summarizes the mechanism of action of Huanglian Wendan decoction in improving lipid accumulation by regulating lipid metabolism， ameliorating insulin resistance， and exerting an anti-inflammatory effect， as well as the pharmacological actions of related active components， in order to provide a theoretical basis for the clinical application of Huanglian Wendan decoction in the management of MAFLD.
-
图 1 脂质堆积与其影响因素的作用关系
Figure 1. The interplay between lipid accumulation and contributing factors
注： PPARα，过氧化物酶体增殖物激活受体α；CPT1，肉碱棕榈酰转移酶1；LXRα，肝X受体α；ABCA1，三磷酸腺苷结合盒转运蛋白A1；CYP7A1，细胞色素P450家族7亚家族A成员1；SREBP-1c，固醇调节元件结合蛋白1c。
图 2 黄连温胆汤通过调节脂质代谢改善脂质堆积的作用机制
Figure 2. Mechanism by which Huanglian Wendan decoction improves lipid accumulation via lipid metabolism regulation
注： SCFA，短链脂肪酸；GPR41/43，G蛋白偶联受体41/43；GLP1，胰高血糖素样肽1；PYY，YY肽；PI3K/Akt，磷脂酰肌醇3-激酶/蛋白激酶B；FOXO1，叉头框蛋白O1；GLUT4，葡萄糖转运蛋白4。
图 3 黄连温胆汤通过胰岛素抵抗改善脂质堆积的作用机制
Figure 3. Mechanism by which Huanglian Wendan decoction reduces lipid accumulation via amelioration of insulin resistance
注： NLRP3，核苷酸结合寡聚结构域样受体家族热蛋白结构域相关蛋白3；Caspase-1，胱天蛋白酶1；TGR5，G蛋白偶联胆汁酸受体1；NF-κB，核因子κB；PPARα，过氧化物酶体增殖物激活受体α；TLR4，Toll样受体4；LPS，脂多糖。
图 4 黄连温胆汤通过抗炎改善脂质堆积的作用机制
Figure 4. Mechanism by which Huanglian Wendan decoction reduces lipid accumulation via anti-inflammatory action
表 1 黄连温胆汤主要活性成分的药理作用
Table 1. Pharmacological actions of the main active constituents of Huanglian Wendan decoction
活性成分 归属中药 靶点/通路/途径 具体效应 参考文献 半夏水提取物 半夏 ATGL↑ 促进脂质分解 ［39］ 荭草素 竹茹 PI3K/Akt↑，P38/MAPK↑，参与GLUT2转运 改善胰岛素抵抗 ［40-41］ 新橙皮苷、柚皮苷 枳实 NF-κB↓ 抗炎 ［42］ 茯苓提取物 茯苓 PPARα↑，SREBP-1c↓ 调节脂质代谢 ［43］ 甘草查尔酮A 甘草 NF-κB↓ 抗炎 ［44］ 姜辣素 生姜 PI3K/Akt↑ 改善胰岛素抵抗 ［45］ 小檗碱 黄连 SREBP-1c↓ 抑制脂质合成 ［16］ 注：ATGL，脂肪甘油三酯脂肪酶；PI3K，磷脂酰肌醇3-激酶；Akt，蛋白激酶B；P38/MAPK，促分裂原活化的蛋白质激酶；GLUT2，葡萄糖转运蛋白2；NF-κB，核因子κB；PPARα，过氧化物酶体增殖物激活受体α；SREBP-1c，固醇调节元件结合蛋白1c。
下载: 导出CSV
-
[1] LOU TW, YANG RX, FAN JG. The global burden of fatty liver disease: The major impact of China[J]. Hepatobiliary Surg Nutr, 2024, 13( 1): 119- 123. DOI: 10.21037/hbsn-23-556. [2] XIAO QQ, WANG MY, FAN JG. Brief introduction of APASL clinical practice guidelines on metabolic associated fatty liver disease(Treatment Part)[J]. J Clin Hepatol, 2021, 37( 1): 41- 45. DOI: 10.3969/j.issn.1001-5256.2021.01.009.肖倩倩, 王梦雨, 范建高. 亚太肝病研究学会代谢相关脂肪性肝病临床诊疗指南(治疗部分)简介[J]. 临床肝胆病杂志, 2021, 37( 1): 41- 45. DOI: 10.3969/j.issn.1001-5256.2021.01.009. [3] Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of metabolic dysfunction-associated(non-alcoholic) fatty liver disease(Version 2024)[J]. J Prac Hepatol, 2024, 27( 4): 494- 510. DOI: 10.3760/cma.j.cn501113-20240327-00163.中华医学会肝病学分会. 代谢相关(非酒精性)脂肪性肝病防治指南(2024年版)[J]. 实用肝脏病杂志, 2024, 27( 4): 494- 510. DOI: 10.3760/cma.j.cn501113-20240327-00163. [4] ZHOU Q, TAO L, ZHANG SS. TCM recognition and treatment of metabolic associated fatty liver disease[J]. China J Tradit Chin Med Pharm, 2021, 36( 11): 6380- 6384.周强, 陶琳, 张声生. 代谢相关脂肪性肝病的中医认识及辨治[J]. 中华中医药杂志, 2021, 36( 11): 6380- 6384. [5] HE YQ, LU ZH. Study on the efficacy and safety of oral administration of Wuling Capsules in patients with metabolic dysfunction-associated fatty liver disease[J]. Northwest Pharm J, 2024, 39( 5): 10- 17. DOI: 10.3969/j.issn.1004-2407.2024.05.002.何煜钦, 陆忠华. 口服五灵胶囊治疗代谢相关脂肪性肝病的疗效及安全性研究[J]. 西北药学杂志, 2024, 39( 5): 10- 17. DOI: 10.3969/j.issn.1004-2407.2024.05.002. [6] YU LY, LI WY, LIN J. Juglanin improves lipid metabolism disorder, liver injury, and intestinal integrity in nonalcoholic fatty liver mice[J]. World Chin J Dig, 2020( 4): 113- 121. DOI: 10.11569/wcjd.v28.i4.113.虞玲燕, 李卫英, 林佳. 胡桃苷对非酒精性脂肪性肝小鼠中肝脂质代谢紊乱、肝损伤以及小肠完整性的改善作用[J]. 世界华人消化杂志, 2020( 4): 113- 121. DOI: 10.11569/wcjd.v28.i4.113. [7] ZHANG YT, WANG AH, YANG JN, et al. Mechanisms of cholesterol metabolism imbalance in a PA-induced non-alcoholic fatty liver disease cell model[J]. J China Pharm Univ, 2023, 54( 4): 490- 500. DOI: 10.11665/j.issn.1000-5048.2023032401.章玉婷, 王安慧, 杨晋妮, 等. 非酒精性脂肪性肝病细胞模型中胆固醇代谢紊乱机制[J]. 中国药科大学学报, 2023, 54( 4): 490- 500. DOI: 10.11665/j.issn.1000-5048.2023032401. [8] PENG KP, MO ZN, TIAN GX. Serum lipid abnormalities and nonalcoholic fatty liver disease in adult males[J]. Am J Med Sci, 2017, 353( 3): 236- 241. DOI: 10.1016/j.amjms.2017.01.002. [9] SUI YB. Intervention effect of Huanglian Wendan decoction on NF-κB, PPARα and glucose and lipid metabolism in rats with metabolic syndrome[D]. Harbin: Heilongjiang University of Chinese Medicine, 2011.隋艳波. 黄连温胆汤对代谢综合征大鼠NF-κB、PPARα及糖脂代谢调控的干预作用[D]. 哈尔滨: 黑龙江中医药大学, 2011. [10] LI YT. The mechanism of the optimal dose of Huanglian in Huanglian Wendan decoction through the liver lipid matabolism signal pathway PPARα-LXRα-ABCA1 in T2DM rats[D]. Harbin: Heilongjiang University of Chinese Medicine, 2018.李雨庭. 黄连温胆汤中黄连最佳剂量对T2DM大鼠肝脏脂代谢PPARα- LXRα-ABCA1信号通路的影响[D]. 哈尔滨: 黑龙江中医药大学, 2018. [11] CHINETTI G, LESTAVEL S, BOCHER V, et al. PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway[J]. Nat Med, 2001, 7( 1): 53- 58. DOI: 10.1038/83348. [12] COSTET P, LUO Y, WANG N, et al. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor[J]. J Biol Chem, 2000, 275( 36): 28240- 28245. DOI: 10.1074/jbc.M003337200. [13] YU W, ZHANG GF, ZHEN JL, et al. Effect of Lonicera caerulea anthocyan on the role of cholesterol metabolism related genes in the liver of hyperlipidemic rats[J]. Food Sci, 2018, 39( 17): 171- 176.于伟, 张桂芳, 甄井龙, 等. 蓝靛果花色苷对高脂血症大鼠肝脏内与胆固醇代谢相关基因的作用[J]. 食品科学, 2018, 39( 17): 171- 176. [14] SCHULTZ JR, TU H, LUK A, et al. Role of LXRs in control of lipogenesis[J]. Genes Dev, 2000, 14( 22): 2831- 2838. DOI: 10.1101/gad.850400. [15] LI YP, ZANG CY. Effects of Wendan Decoction on lipid metabolism in mice with metabolism-related fatty liver disease[J]. Tianjin J Tradit Chin Med, 2023, 40( 8): 1035- 1042. DOI: 10.11656/j.issn.1672-1519.2023.08.16.李昱芃, 臧超越. 温胆汤对代谢相关脂肪性肝病小鼠脂质代谢的影响[J]. 天津中医药, 2023, 40( 8): 1035- 1042. DOI: 10.11656/j.issn.1672-1519.2023.08.16. [16] GE YB, ZHANG Y, LI R, et al. Berberine regulated Gck, G6pc, Pck1 and Srebp-1c expression and activated AMP-activated protein kinase in primary rat hepatocytes[J]. Int J Biol Sci, 2011, 7( 5): 673- 684. DOI: 10.7150/ijbs.7.673. [17] XIONG Y, LI X, LIU CY, et al. Exploring the association between insulin resistance surrogates(estimated glucose disposal rate, insulin resistance metabolic score, triglyceride glucose index-related parameters) and metabolism-related fatty liver disease[J]. Mod Interv Diagn Treat Gastroenterol, 2024, 29( 11): 1281- 1293. DOI: 10.3969/j.issn.1672-2159.2024.11.004.熊洋, 李翔, 刘晨瑶, 等. 胰岛素抵抗替代指标与代谢性相关脂肪性肝病的关联性探究[J]. 现代消化及介入诊疗, 2024, 29( 11): 1281- 1293. DOI: 10.3969/j.issn.1672-2159.2024.11.004. [18] YU SR, LIU CL, ZHONG YB, et al. Effects of Wendan Decoction on glucolipid metabolism and PI3K/Akt signaling pathway in obese rats with phlegm and dampness syndrome[J]. China J Tradit Chin Med Pharm, 2024, 39( 10): 5468- 5473.喻松仁, 刘彩玲, 钟友宝, 等. 温胆汤对肥胖痰湿证大鼠糖脂代谢及PI3K/Akt信号通路的影响[J]. 中华中医药杂志, 2024, 39( 10): 5468- 5473. [19] SAMUEL VT, SHULMAN GI. Mechanisms for insulin resistance: Common threads and missing links[J]. Cell, 2012, 148( 5): 852- 871. DOI: 10.1016/j.cell.2012.02.017. [20] LI XH, MONKS B, GE QY, et al. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator[J]. Nature, 2007, 447( 7147): 1012- 1016. DOI: 10.1038/nature05861. [21] BROWN MS, GOLDSTEIN JL. Selective versus total insulin resistance: A pathogenic paradox[J]. Cell Metab, 2008, 7( 2): 95- 96. DOI: 10.1016/j.cmet.2007.12.009. [22] DAN NL. Effects of Huanglian Wendan Decoction on liver tissue and PI3K/Akt signaling pathway in T2DM mice[D]. Chengdu: Chengdu Institute of Physical Education, 2021.但柟林. 黄连温胆汤对T2DM小鼠肝脏组织和PI3K/Akt信号通路的影响[D]. 成都: 成都体育学院, 2021. [23] PANG LR, LI SM. Effect and mechanism of Huanglian Wendan decoction on glucose and lipid metabolism in rats with metabolic syndrome[J]. J Guangzhou Univ Tradit Chin Med, 2019, 36( 5): 714- 718.庞琳蓉, 李赛美. 黄连温胆汤改善代谢综合征大鼠糖脂代谢的作用及机制研究[J]. 广州中医药大学学报, 2019, 36( 5): 714- 718. [24] LETO D, SALTIEL AR. Regulation of glucose transport by insulin: Traffic control of GLUT4[J]. Nat Rev Mol Cell Biol, 2012, 13( 6): 383- 396. DOI: 10.1038/nrm3351. [25] HAN YB. Research on the intervention mechanism of Huanglian Wendan Decoction on PI3K/Akt signaling pathway of 3T3-L1 adipocytes[D]. Harbin: Heilongjiang University of Chinese Medicine, 2018.韩宇博. 黄连温胆汤对3T3-L1脂肪细胞PI3K/Akt信号通路的干预机制研究[D]. 哈尔滨: 黑龙江中医药大学, 2018. [26] XIONG QY, ZOU HH, WANG YH, et al. Mechanism and intervention effect of Huanglian Wendan Tang on type 2 diabetes mellitus in rats by regulating SCFAs-GPR41/43-GLP1 signaling pathway[J]. Pharmacol Clin Chin Mater Med, 2023, 39( 12): 2- 7.熊秋迎, 邹海虹, 王雨豪, 等. 黄连温胆汤调控SCFAs-GPR41/43-GLP1信号通路干预2型糖尿病模型大鼠的作用机制[J]. 中药药理与临床, 2023, 39( 12): 2- 7. [27] YIN L. The impact of inflammatory stress on FAT/CD36Expression and lipid accumulation in livers[D]. Chongqing: Chongqing Medical University, 2013.殷鹭. 炎症对肝脏FAT/CD36的表达及脂质积聚的影响[D]. 重庆: 重庆医科大学, 2013. [28] SZABO G, PETRASEK J. Inflammasome activation and function in liver disease[J]. Nat Rev Gastroenterol Hepatol, 2015, 12( 7): 387- 400. DOI: 10.1038/nrgastro.2015.94. [29] WREE A, EGUCHI A, MCGEOUGH MD, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice[J]. Hepatology, 2014, 59( 3): 898- 910. DOI: 10.1002/hep.26592. [30] MA BY, XIN XR, LU GL, et al. Mechanism of Huanglian Wendantang in improving IR-HepG2 based on NLRP3/caspase-1 signaling pathway[J]. Chin J Exp Tradit Med Formulae, 2022, 28( 18): 1- 11. DOI: 10.13422/j.cnki.syfjx.20221301.马伯艳, 辛相如, 陆阁玲, 等. 基于NLRP3/Caspase-1信号通路探讨黄连温胆汤改善HepG2细胞胰岛素抵抗的作用机制[J]. 中国实验方剂学杂志, 2022, 28( 18): 1- 11. DOI: 10.13422/j.cnki.syfjx.20221301. [31] THOMAS C, GIOIELLO A, NORIEGA L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis[J]. Cell Metab, 2009, 10( 3): 167- 177. DOI: 10.1016/j.cmet.2009.08.001. [32] XU X, OTSUKI M, SAITO H, et al. PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells[J]. Endocrinology, 2001, 142( 8): 3332- 3339. DOI: 10.1210/endo.142.8.8340. [33] WANG YJ, QIE YL, JIANG H, et al. Mechanism of Huanglian Wendantang on damp-heat type diabetes enteropathy rats based on TGR5/GLP-1 signaling pathway and intestinal flora[J]. Chin J Exp Tradit Med Formulae, 2025, 31( 15): 10- 18. DOI: 10.13422/j.cnki.syfjx.20242243.王郁金, 伽雨龙, 姜华, 等. 基于TGR5/GLP-1信号通路和肠道菌群探讨黄连温胆汤对湿热型糖尿病肠病大鼠的作用机制[J]. 中国实验方剂学杂志, 2025, 31( 15): 10- 18. DOI: 10.13422/j.cnki.syfjx.20242243. [34] RAO C, XIAO XH. Intestinal microbiota and lipid metabolic disorders[J/OL]. Chin J Clin Electron Ed, 2016, 10( 8): 1018- 1022. DOI: 10.3877/cma.j.issn.1674-0785.2016.08.001.饶翀, 肖新华. 肠道菌群和脂代谢异常[J/OL]. 中华临床医师杂志(电子版), 2016, 10( 8): 1018- 1022. DOI: 10.3877/cma.j.issn.1674-0785.2016.08.001. [35] ZHOU J, SUN TZ, JIN SH, et al. Dual feedforward loops modulate type I interferon responses and induce selective gene expression during TLR4 activation[J]. iScience, 2020, 23( 2): 100881. DOI: 10.1016/j.isci.2020.100881. [36] ZHU JH, ZHOU J, WAN HJ, et al. Effects of Huanglian Wendan decoction on cytokines, TLR4 and NF-κB in rats with T2DM[J]. Pharmacol Clin Chin Mater Med, 2021, 37( 3): 6- 11.朱金华, 周军, 万红娇, 等. 黄连温胆汤对2型糖尿病模型大鼠细胞因子及TLR4、NF-κB变化的影响[J]. 中药药理与临床, 2021, 37( 3): 6- 11. [37] CHEN YX, WAN HJ, ZHU JH, et al. Effect of Huanglian Wendan Tang on FBG, INS and gut microbiota in rats with T2D[J]. Pharmacol Clin Chin Mater Med, 2019, 35( 3): 2- 7.陈亚昕, 万红娇, 朱金华, 等. 黄连温胆汤对2型糖尿病模型鼠空腹血糖、INS及肠道菌群变化的影响[J]. 中药药理与临床, 2019, 35( 3): 2- 7. [38] YUAN YD, JIANG SJ, ZHANG YL. Research progress in the treatment of metabolic related diseases with Wendan decoction and its modified formulas[J]. J Changchun Univ Chin Med, 2025, 41( 3): 328- 333. DOI: 10.13463/j.cnki.cczyy.2025.03.021.袁雅丹, 蒋淑君, 张彦亮. 温胆汤及其加减方治疗代谢相关性疾病的研究进展[J]. 长春中医药大学学报, 2025, 41( 3): 328- 333. DOI: 10.13463/j.cnki.cczyy.2025.03.021. [39] LEE H, KIM MH, JIN SC, et al. Lipolytic and lipophagic effects of Pinellia ternata pharmacopuncture on localized adiposity[J]. Evid Based Complementary Altern Med, 2021, 2021: 7347639. DOI: 10.1155/2021/7347639. [40] MAZIBUKO-MBEJE SE, MTHEMBU SXH, TSHIITAMUNE A, et al. Orientin improves substrate utilization and the expression of major genes involved in insulin signaling and energy regulation in cultured insulin-resistant liver cells[J]. Molecules, 2021, 26( 20): 6154. DOI: 10.3390/molecules26206154. [41] LI FH, LIAO X, JIANG L, et al. Orientin attenuated d-GalN/LPS-induced liver injury through the inhibition of oxidative stress via Nrf2/Keap1 pathway[J]. J Agric Food Chem, 2022, 70( 26): 7953- 7967. DOI: 10.1021/acs.jafc.2c02015. [42] SHI Q, SONG XF, FU JL, et al. Artificial sweetener neohesperidin dihydrochalcone showed antioxidative, anti-inflammatory and anti-apoptosis effects against paraquat-induced liver injury in mice[J]. Int Immunopharmacol, 2015, 29( 2): 722- 729. DOI: 10.1016/j.intimp.2015.09.003. [43] HE J, YANG Y, ZHANG F, et al. Effects of Poria cocos extract on metabolic dysfunction-associated fatty liver disease via the FXR/PPARα-SREBPs pathway[J]. Front Pharmacol, 2022, 13: 1007274. DOI: 10.3389/fphar.2022.1007274. [44] LV HM, YANG HH, WANG ZF, et al. Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A[J]. Cell Death Dis, 2019, 10( 4): 313. DOI: 10.1038/s41419-019-1543-z. [45] CHEN MX, WANG N, MENG FQ, et al. Isolation of gingerols and its preventive effect on insulin resistance of HepG2 cells[J]. Sci Technol Food Ind, 2022, 43( 22): 387- 395. DOI: 10.13386/j.issn1002-0306.2022030039.陈梦霞, 汪妮, 孟凡强, 等. 生姜姜辣素的分离及对HepG2细胞胰岛素抵抗的预防作用[J]. 食品工业科技, 2022, 43( 22): 387- 395. DOI: 10.13386/j.issn1002-0306.2022030039. -
本文二维码
图(4) / 表(1)
计量
- 文章访问数: 12
- HTML全文浏览量: 4
- PDF下载量: 4
- 被引次数: 0
