PPARγ在肝纤维化进程中的影响及其配体药物研发进展

doi:10.19803/j.1672-8629.20230537

中国药物警戒 ›› 2024, Vol. 21 ›› Issue (6): 716-720.
DOI: 10.19803/j.1672-8629.20230537

• 综述 • 上一篇

PPARγ在肝纤维化进程中的影响及其配体药物研发进展

赵晓璐, 高晓阳, 张春艳, 李明奇, 马月宏^*

内蒙古医科大学基础医学院,内蒙古呼和浩特,010110

收稿日期:2023-09-01 出版日期:2024-06-15 发布日期:2024-06-18
通讯作者: ^*马月宏,男,教授·硕导,中蒙药抗纤维化药理。E-mial:myh19982002@sina.com
作者简介:赵晓璐,女,在读硕士,中蒙药抗纤维化药理。
基金资助:
国家自然科学基金资助项目（81960759、81560706）; 内蒙古自治区自然科学基金资助项目（2019MS08010、2014MS0841）; 内蒙古自治区草原英才培养计划; 内蒙古医科大学致远人才项目（ZY0201012）; 内蒙古人才开发基金（22056）; 内蒙古医科大学重点项目（YKD2022ZD019）; 内蒙古医科大学蒙药抗肝纤维化作用研究科技创新团队（YKD2022TD039）

Effect of PPARγ in liver fibrosis and current development of its ligand drugs: research progress

ZHAO Xiaolu, GAO Xiaoyang, ZHANG Chunyan, LI Mingqi, MA Yuehong^*

Department of Basic Medicine, Inner Mongolia Medical University, Hohhot Inner Mongolia 010110, China

Received:2023-09-01 Online:2024-06-15 Published:2024-06-18

摘要/Abstract

摘要： 过氧化物酶体增殖激活受体（peroxisome proliferator-activated receptors, PPARs）是由内源性或外源性配体激活的核因子家族成员之一,是调节脂肪生成与代谢、炎症以及与其他转录因子信号等串扰在纤维化进程的调节剂,是近年来较有潜力的一个治疗靶点。肝纤维化（hepatic fibrosis, HF）是由多种病因导致的以胶原沉积、细胞外基质（extracellular matrix, ECM）增多为主的复杂病理变化,活化的肝星状细胞（hepatic stellate cells, HSCs）是其中心环节,随着对PPARs研究发现其亚型PPARγ在脂肪组织、巨噬细胞与HSCs的表达共同参与炎症反应等,进而导致肝纤维化的形成,其上调在逆转肝纤维化中维持HSCs静止表型及促使活化HSCs凋亡也起一定作用,表明以PPARγ为靶点激活的配体药物可能在抗纤维化治疗中扮演重要角色。

关键词: 氧化物酶体增殖激活受体, PPARγ, 肝纤维化, 肝星状细胞, 配体药物, 药物研发

Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear factor family activated by endogenous or exogenous ligands, which regulate adipogenesis and metabolism, inflammation and other transcriptional modulators of crosstalk such as factor signaling in fibrosis progression. They have become a promising therapeutic target in recent years. Hepatic fibrosis (HF) is a complex pathological change mainly caused by collagen deposition and extracellular matrix (ECM) increases due to various etiologies, in which activated hepatic stellate cells (HSCs) play a pivotal role. Studies on PPARs have found that the expressions of its isoform PPARγ in adipose tissue, macrophages and HSCs are involved in inflammation, which leads to the formation of liver fibrosis. The upregulation of PAARγ maintains HSCs in reversing liver fibrosis. The quiescent phenotype and the promotion of apoptosis of activated HSCs also make a difference, suggesting that ligand-activated drugs targeting PAARγ may play an important role in anti-fibrotic therapy.

Key words: PPARs, PPARγ, liver fibrosis, hepatic stellate cells, ligand drug, drug development

中图分类号:

R976

赵晓璐, 高晓阳, 张春艳, 李明奇, 马月宏. PPARγ在肝纤维化进程中的影响及其配体药物研发进展[J]. 中国药物警戒, 2024, 21(6): 716-720.

ZHAO Xiaolu, GAO Xiaoyang, ZHANG Chunyan, LI Mingqi, MA Yuehong. Effect of PPARγ in liver fibrosis and current development of its ligand drugs: research progress[J]. Chinese Journal of Pharmacovigilance, 2024, 21(6): 716-720.

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参考文献

[1] ROEHLEN N, CROUCHET E, BAUMERT TF.Liver fibrosis: mechanistic concepts and therapeutic perspectives[J]. Cells, 2020, 9(4): 875.
[2] CHEN H, TAN H, WAN J, et al.PPAR-γ signaling in nonalcoholic fatty liver disease: pathogenesis and therapeutic targets[J]. Pharmacol Ther, 2023, 245: 108391.
[3] PU S, ZHOU H, LIU Y, et al.Roles of nuclear receptors in hepatic stellate cells[J]. Expert Rev Gastroenterol Hepatol, 2021, 15(8): 879-890.
[4] HALLENBORG P, PETERSEN RK, KOUSKOUMVEKAKI I, et al.The elusive endogenous adipogenic PPARγ agonists: lining up the suspects[J]. Prog Lipid Res, 2016, 61: 149-162.
[5] MIRZA AZ, ALTHAGAFI II, SHAMSHAD H.Role of PPAR receptor in different diseases and their ligands: physiological importance and clinical implications[J]. European Journal of Medicinal Chemistry: Chimie Therapeutique, 2019(166): 502-513.
[6] WAGNER KD, DU S, MARTIN L, et al.Vascular PPARβ/δ promotes tumor angiogenesis and progression[J]. Cells, 2019, 8(12): 1623.
[7] QIU YY, ZHANG J, ZENG FY, et al.Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)[J]. Pharmacol Res, 2023, 192: 106786.
[8] MATSUDA M, SEKI E.Hepatic stellate cell-macrophage crosstalk in liver fibrosis and carcinogenesis[J]. Semin Liver Dis, 2020, 40(3): 307-320.
[9] WANG Z, DU K, JIN N, et al.Macrophage in liver fibrosis: identities and mechanisms[J]. Int Immunopharmacol, 2023, 120: 110357.
[10] WU HM, NI XX, XU QY, et al.Regulation of lipid-induced macrophage polarization through modulating peroxisome proliferator-activated receptor-gamma activity affects hepatic lipid metabolism via a Toll-like receptor 4/NF-κB signaling pathway[J]. J Gastroenterol Hepatol, 2020, 35(11): 1998-2008.
[11] LI X, JIN Q, YAO Q, et al.The flavonoid quercetin ameliorates liver inflammation and fibrosis by regulating hepatic macrophages activation and polarization in mice[J]. Front Pharmacol, 2018, 9: 72.
[12] ZHOU RJ, YE H, WANG F, et al.Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice[J]. Biochem Biophys Res Commun, 2017, 493(1): 625-630.
[13] YU Q, CHENG P, WU J, et al.PPARγ/NF-κB and TGF-β1/Smad pathway are involved in the anti-fibrotic effects of levo-tetrahydropalmatine on liver fibrosis[J]. J Cell Mol Med, 2021, 25(3): 1645-1660.
[14] CHEN Q, BAO L, LYU L, et al.Schisandrin B regulates macrophage polarization and alleviates liver fibrosis via activation of PPARγ[J]. Ann Transl Med, 2021, 9(19): 1500.
[15] WANG R, SONG FX, LI SN, et al.Salvianolic acid a attenuates CCl4-induced liver fibrosis by regulating the PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways[J]. Drug Design, 2019, 13: 1889-1900.
[16] LIN T, PENG JX, TAO YY, et al. Astragaloside induces autophagy and apoptosis in nasopharyngeal carcinoma cells via PI3K/Akt/mTOR pathway[J/OL]. Chinese Journal of Experimental Formulary(中国实验方剂学杂志). (2023-02-01)[2023-11-03]. https://doi.org/10.13422/j.cnki.syfjx.20230726.
[17] KMA L, TARANGA JB.The interplay of ROS and the PI3K/Akt pathway in autophagy regulation[J].Biotechnology and Applied Biochemistry, 2022, 69(1): 248-264.
[18] HE J, HONG B, BIAN M, et al.Docosahexaenoic acid inhibits hepatic stellate cell activation to attenuate liver fibrosis in a PPARγ-dependent manner[J]. Int Immunopharmacol, 2019, 75: 105816.
[19] SONODA S, MURATA S, YAMAZA H, et al.Targeting hepatic oxidative stress rescues bone loss in liver fibrosis[J]. Mol Metab, 2022, 66: 101599.
[20] JIN HH.Research on the mechanism of curcumin regulating cellular senescence against liver fibrosis[D]. Nanjing: Nanjing University of Traditional Chinese Medicine, 2018.
[21] ZHANG M, SERNA-SALAS S, DAMBA T, et al.Hepatic stellate cell senescence in liver fibrosis: characteristics, mechanisms and perspectives[J]. Mech Ageing Dev, 2021, 199: 111572.
[22] YU H, JIANG X, DONG F, et al.Lipid accumulation-induced hepatocyte senescence regulates the activation of hepatic stellate cells through the Nrf2-antioxidant response element pathway[J]. Exp Cell Res, 2021, 405(2): 112689.
[23] LIU YY.The study on mechanism of the active vitamin D in improving nonalcoholic fatty liver disease by regulating the p53-p21 pathway to reduce cell senescence[D]. Suzhou: Soochow University, 2020.
[24] JIN H, LIAN N, ZHANG F, et al.Activation of PPARγ /p53 signaling is required for curcumin to induce hepatic stellate cell senescence[J]. Cell Death Dis, 2016, 7: e2189.
[25] SCHAFER MJ, HAAK AJ, TSCHUMPERLIN DJ, et al.Targeting senes-cent cells in fibrosis: pathology, paradox, and practical consider-ations[J]. Curr Rheumatol Rep, 2018, 20: 3.
[26] ZHANG Z, YANG P, ZHAO J.Ferulic acid mediates prebiotic responses of cereal-derived arabinoxylans on host health[J]. Animal Nutrition, 2021, 9: 31-38.
[27] LIU YL, WANG YR, ZHANG QZ.Progress in the study of intestinal flora-peroxisome proliferator-activated receptor signalling pathway and its role in the pathogenesis of metabolism-associated fatty liver disease[J]. Shaanxi Medical Journal, 2021, 50(9): 1166-1169.
[28] DE VOS WM, TILG H, VAN HUL M, et al.Gut microbiome and health: mechanistic insights[J]. Gut, 2022, 71(5): 1020-1032.
[29] SEIRI P, ABI A, SOUKHTANLOO M.PPARγ: its ligand and its regulation by microRNAs[J]. J Cell Biochem, 2019, 120(7): 10893-10908.
[30] WEI A, GAO Q, CHEN F, et al.Inhibition of DNA methylation de-represses peroxisome proliferator-activated receptor-γ and attenuates pulmonary fibrosis[J]. Br J Pharmacol, 2022, 179(7): 1304-1318.
[31] MCVICKER BL, HAMEL FG, SIMPSON RL, et al.A selective PPARγ modulator reduces hepatic fibrosis[J]. Biology, 2020, 9(7): 151.
[32] MCVICKER BL, SIMPSON RL, HAMELlFG, et al. Reduction in obesity-related hepatic fibrosis by SR1664[J]. Biology (Basel), 2023, 12(10): 1287.
[33] BOYER-DIAZ Z, ARISTU-ZABALZA P, ANDRÉS-ROZAS M, et al. Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease[J]. J Hepatol, 2021, 74(5): 1188-1199.
[34] CHHIMWAL J, SHARMA S, KULURKAR P, et al.Crocin attenuates CCl4-induced liver fibrosis via PPAR-γ mediated modulation of inflammation and fibrogenesis in rats[J]. Hum Exp Toxicol, 2020, 39(12): 1639-1649.
[35] XIONG K, SHI M, ZHANG T, et al.Protective effect of picroside I against hepatic fibrosis in mice via sphingolipid metabolism, bile acid biosynthesis, and PPAR signaling pathway[J]. Biomed Pharmacother, 2020, 131: 110683.
[36] TAO L, WU L, ZHANG W, et al.Peroxisome proliferator-activated receptorγinhibits hepatic stellate cell activation regulated by miR-942 in chronic hepatitis B liver fibrosis[J]. Life Sciences, 2020, 253: 117572.

PPARγ在肝纤维化进程中的影响及其配体药物研发进展

Effect of PPARγ in liver fibrosis and current development of its ligand drugs: research progress

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