肝纤维化相关信号通路及其相应的抗肝纤维化药物研究进展

鲁苏日古嘎; 刘霆; 朱单单; 余思佳; 卢礼卿; 丁俊杰

doi:10.3969/j.issn.1001-5256.2022.05.039

肝纤维化相关信号通路及其相应的抗肝纤维化药物研究进展

DOI: 10.3969/j.issn.1001-5256.2022.05.039

中南大学湘雅医院，长沙 410000

基金项目:

国家自然科学基金 (82070632)

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：鲁苏日古嘎负责资料收集及文章撰写; 朱单单、刘霆、卢礼卿、余思佳、丁俊杰参与修改文章内容。

详细信息

通信作者:
刘霆，liuting818@126.com

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出版历程
- 收稿日期: 2021-09-07
- 出版日期: 2022-05-20

Research advances in hepatic fibrosis related signal pathways and anti-hepatic fibrosis drugs

Xiangya Hospital of Central South University, Changsha 410000, China

Research funding:

National Natural Science Foundation of China (82070632)

More Information

Corresponding author: LIU Ting, liuting818@126.com (ORCID: 0000-0001-8178-6532)

摘要

摘要: 肝纤维化是肝脏长期受到各种急、慢性损伤导致肝星状细胞激活、细胞外基质生成与降解失衡并在肝脏沉积的一种病理学过程，受多条细胞信号转导通路和一系列细胞信息分子网络共同控制。如未行有效的治疗干预，随着病情的发展形成肝纤维结节并破坏正常的肝脏结构与功能，最终发展为肝硬化，出现肝功能的衰退，甚至演变为肝癌。本文着重介绍目前研究较明确和相对热点的肝纤维化信号通路、受体、非编码RNA及其对应的抗肝纤维化药物/分子的研究进展。
- 肝硬化 /
- 肝星状细胞 /
- 信号传导 /
- 药物疗法
Abstract: Hepatic fibrosis is a pathological process in which the liver is subjected to various acute and chronic injuries for a long time, resulting in activation of hepatic stellate cells, the imbalance between the production and degradation of extracellular matrix, and the deposition of extracellular matrix in the liver, and it is jointly controlled by multiple cellular signal transduction pathways and a series of cellular information molecular networks. If there is no effective treatment, with the progression of the disease, liver fibrous nodules will form, destroy normal liver structure and function, and finally develop into liver cirrhosis, the decline of liver function, and even liver cancer. This article summarizes the research advances in the signaling pathways, receptors, and non-coding RNAs involved in liver fibrosis and the corresponding anti-hepatic fibrosis drugs/molecules.
- Liver Cirrhosis /
- Hepatic Stellate Cell /
- Signal Transduction /
- Drug Therapy

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图 1 肝纤维化信号传导通路图

注：多种细胞信号传导通路构成复杂的网络，共同参与了肝纤维化的发生和发展。细胞膜上受体接受信号刺激后，通过其信号通路下游靶点传达信号，最终在细胞核调节多个肝纤维化相关靶基因的表达。miRNA等非编码RNA也参与这些信号传导，或促进或抑制肝纤维化。Col1a1：表达Ⅰ型胶原蛋白; Col3a1：表达Ⅲ型胶原蛋白。

Figure 1. Diagram of hepatic fibrosis signaling pathways

下载: 全尺寸图片幻灯片

参考文献(31)

[1]	HIGASHI T, FRIEDMAN SL, HOSHIDA Y. Hepatic stellate cells as key target in liver fibrosis[J]. Adv Drug Deliv Rev, 2017, 121: 27-42. DOI: 10.1016/j.addr.2017.05.007.
[2]	FRIEDMAN SL. Molecular mechanisms of hepatic fibrosis and principles of therapy[J]. J Gastroenterol, 1997, 32(3): 424-430. DOI: 10.1007/BF02934504.
[3]	DERYNCK R, BUDI EH. Specificity, versatility, and control of TGF-β family signaling[J]. Sci Signal, 2019, 12(570): eaav5183. DOI: 10.1126/scisignal.aav5183.
[4]	LIU J, KONG D, QIU J, et al. Praziquantel ameliorates CCl₄-induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells[J]. Br J Pharmacol, 2019, 176(24): 4666-4680. DOI: 10.1111/bph.14831.
[5]	NI XX, LI XY, WANG Q, et al. Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-β1/Smad signaling pathway[J]. J Physiol Biochem, 2021, 77(1): 35-45. DOI: 10.1007/s13105-020-00777-7.
[6]	OGAWA H, KAJI K, NISHIMURA N, et al. Lenvatinib prevents liver fibrosis by inhibiting hepatic stellate cell activation and sinusoidal capillarization in experimental liver fibrosis[J]. J Cell Mol Med, 2021, 25(8): 4001-4013. DOI: 10.1111/jcmm.16363.
[7]	ZHANG W, YANG GY, SHEN DX, et al. Mechanism of action of Xiayuxue decoction in inhibiting liver fibrosis by regulating glial cell line -derived neurotrophic factor[J]. J Clin Hepatol, 2021, 37(3): 575-581. DOI: 10.3969/j.issn.1001-5256.2021.03.015. 张玮, 杨广越, 沈东晓, 等. 下瘀血汤抑制胶质细胞源性神经营养因子抗肝纤维化的作用机制[J]. 临床肝胆病杂志, 2021, 37(3): 575-581. DOI: 10.3969/j.issn.1001-5256.2021.03.015.
[8]	CHOI S, JUNG HJ, KIM MW, et al. A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice[J]. Biochem Biophys Res Commun, 2019, 513(1): 49-55. DOI: 10.1016/j.bbrc.2019.03.156.
[9]	LYU L, YIN JK, ZHANG Z, et al. Role of ruxolitinib in the target inhibition of hepatic stellate cell activation and mechanism[J]. J Shanxi Med Univ, 2020, 51(2): 141-146. DOI: 10.13753/j.issn.1007-6611.2020.02.007. 律玲, 阴继凯, 张章, 等. 芦可替尼靶向抑制肝星状细胞活化的作用及机制[J]. 山西医科大学学报, 2020, 51(2): 141-146. DOI: 10.13753/j.issn.1007-6611.2020.02.007.
[10]	SU TH, SHIAU CW, JAO P, et al. Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition[J]. Proc Natl Acad Sci U S A, 2015, 112(23): 7243-7248. DOI: 10.1073/pnas.1507499112.
[11]	DENG YR, MA HD, TSUNEYAMA K, et al. STAT3-mediated attenuation of CCl₄-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib[J]. J Autoimmun, 2013, 46: 25-34. DOI: 10.1016/j.jaut.2013.07.008.
[12]	MARTÍ-RODRIGO A, ALEGRE F, MORAGREGA ÁB, et al. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells[J]. Gut, 2020, 69(5): 920-932. DOI: 10.1136/gutjnl-2019-318372.
[13]	PERUGORRIA MJ, OLAIZOLA P, LABIANO I, et al. Wnt-β-catenin signalling in liver development, health and disease[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(2): 121-136. DOI: 10.1038/s41575-018-0075-9.
[14]	RAO S, XIANG J, HUANG J, et al. PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis[J]. Cell Biosci, 2019, 9: 100. DOI: 10.1186/s13578-019-0363-2.
[15]	RONG X, LIU J, YAO X, et al. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway[J]. Stem Cell Res Ther, 2019, 10(1): 98. DOI: 10.1186/s13287-019-1204-2.
[16]	ZHANG M, HAUGHEY M, WANG NY, et al. Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs[J]. PLoS One, 2020, 15(3): e0229445. DOI: 10.1371/journal.pone.0229445.
[17]	ZHU C, KIM K, WANG X, et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis[J]. Sci Transl Med, 2018, 10(468): eaat0344. DOI: 10.1126/scitranslmed.aat0344.
[18]	RICHTER LR, WAN Q, WEN D, et al. Targeted delivery of Notch inhibitor attenuates obesity-induced glucose intolerance and liver fibrosis[J]. ACS Nano, 2020, 14(6): 6878-6886. DOI: 10.1021/acsnano.0c01007.
[19]	ESMAIL MM, SAEED NM, MICHEL HE, et al. The ameliorative effect of niclosamide on bile duct ligation induced liver fibrosis via suppression of NOTCH and Wnt pathways[J]. Toxicol Lett, 2021, 347: 23-35. DOI: 10.1016/j.toxlet.2021.04.018.
[20]	DAVEY MG, MCTEIR L, BARRIE AM, et al. Loss of cilia causes embryonic lung hypoplasia, liver fibrosis, and cholestasis in the talpid3 ciliopathy mutant[J]. Organogenesis, 2014, 10(2): 177-185. DOI: 10.4161/org.28819.
[21]	GU S, YAN M, WANG C, et al. Microcystin-leucine-arginine induces liver fibrosis by activating the Hedgehog pathway in hepatic stellate cells[J]. Biochem Biophys Res Commun, 2020, 533(4): 770-778. DOI: 10.1016/j.bbrc.2020.09.075.
[22]	FENG J, WANG C, LIU T, et al. Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the Hedgehog pathway during liver fibrosis[J]. J Cell Mol Med, 2019, 23(9): 6479-6493. DOI: 10.1111/jcmm.14543.
[23]	SHEN JY, YAN JY, WEI XZ, et al. Gant61 ameliorates CCl₄-induced liver fibrosis by inhibition of Hedgehog signaling activity[J]. Toxicol Appl Pharmacol, 2020, 387: 114853. DOI: 10.1016/j.taap.2019.114853.
[24]	FIORUCCI S, ANTONELLI E, RIZZO G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis[J]. Gastroenterology, 2004, 127(5): 1497-1512. DOI: 10.1053/j.gastro.2004.08.001.
[25]	FIORUCCI S, RIZZO G, ANTONELLI E, et al. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis[J]. J Pharmacol Exp Ther, 2005, 314(2): 584-595. DOI: 10.1124/jpet.105.084905.
[26]	YOUNOSSI Z M, RATZIU V, LOOMBA R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial[J]. Lancet, 2019, 394(10215): 2184-2196. DOI: 10.1016/S0140-6736(19)33041-7.
[27]	WANG Y, NAKAJIMA T, GONZALEZ FJ, et al. PPARs as metabolic regulators in the liver: Lessons from liver-specific PPAR-null mice[J]. Int J Mol Sci, 2020, 21(6) : 2061. DOI: 10.3390/ijms21062061.
[28]	KLAVDIANOU K, LIOSSIS SN, SAKKAS L, et al. The role of Dickkopf-1 in joint remodeling and fibrosis: A link connecting spondyloarthropathies and scleroderma?[J]. Semin Arthritis Rheum, 2017, 46(4): 430-438. DOI: 10.1016/j.semarthrit.2016.08.014.
[29]	KUMAR DP, CAFFREY R, MARIONEAUX J, et al. The PPAR α/γ agonist saroglitazar improves insulin resistance and steatohepatitis in a diet induced animal model of nonalcoholic fatty liver disease[J]. Sci Rep, 2020, 10(1): 9330. DOI: 10.1038/s41598-020-66458-z.
[30]	MARRA F, DEFRANCO R, ROBINO G, et al. Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis[J]. World J Gastroenterol, 2005, 11(32): 4931-4938. DOI: 10.3748/wjg.v11.i32.4931.
[31]	CHEN W, YAN X, YANG A, et al. miRNA-150-5p promotes hepatic stellate cell proliferation and sensitizes hepatocyte apoptosis during liver fibrosis[J]. Epigenomics, 2020, 12(1): 53-67. DOI: 10.2217/epi-2019-0104.