细胞自噬及其在肝纤维化中的作用

代倩兰; 刘绍能

doi:10.3969/j.issn.1001-5256.2021.06.046

细胞自噬及其在肝纤维化中的作用

DOI: 10.3969/j.issn.1001-5256.2021.06.046

代倩兰,
刘绍能^,

中国中医科学院广安门医院消化内科，北京 100053

基金项目:

国家自然科学基金 (81973832)

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：代倩兰负责查找文献，资料分析，撰写论文；刘绍能负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
代倩兰(1991—)，女，主要从事肝纤维化的基础和临床研究

通信作者:
刘绍能，liushaoneng@126.com

中图分类号: R575.2
计量
- 文章访问数: 901
- HTML全文浏览量: 355
- PDF下载量: 87
- 被引次数: 0
出版历程
- 收稿日期: 2020-11-23
- 录用日期: 2020-12-16
- 出版日期: 2021-06-20

Role of autophagy in liver fibrosis

Qianlan DAI,
Shaoneng LIU^,

Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

摘要

摘要: 自噬是指真核细胞内细胞器、蛋白质等在溶酶体中被降解及其降解产物被重新利用的过程，其对细胞的增殖、分化及稳态起着重要作用。近年来，自噬在肝纤维化中的作用受到越来越多的关注，干预自噬也许成为治疗肝纤维化的新方法。总结了自噬的过程、功能及在肝纤维化中作用，这些研究揭示了自噬对肝纤维化作用机制的复杂性，也启示未来需要找到干预自噬更加可靠、确定的机制和靶点，进而为治疗肝纤维化提供新途径。
- 自噬 /
- 肝硬化 /
- 肝星状细胞
Abstract: Autophagy refers to the process in which organelles and proteins in eukaryocytes are degraded in lysosomes and their degradation products are reused, and it plays an important role in cell proliferation, differentiation, and homeostasis. In recent years, the role of autophagy in liver fibrosis has attracted more and more attention, and intervention of autophagy may become a new method for the treatment of liver fibrosis. This article summarizes the process and function of autophagy and its role in liver fibrosis. These data reveal the complex mechanism of action of autophagy in liver fibrosis and point out the need to find more reliable and definite mechanisms and targets for autophagy intervention in the future, so as to provide new ways for the treatment of liver fibrosis.
- Autophagy /
- Liver Cirrhosis /
- Hepatic Stellate Cell

HTML全文

参考文献(60)

[1]	WYNN TA. Cellular and molecular mechanisms of fibrosis[J]. J Pathol, 2008, 214(2): 199-210. DOI: 10.1002/path.2277.
[2]	HERNANDEZ-GEA V, FRIEDMAN SL. Pathogenesis of liver fibrosis[J]. Annu Rev Pathol, 2011, 6: 425-456. DOI: 10.1146/annurev-pathol-011110-130246.
[3]	TSUCHIDA T, FRIEDMAN SL. Mechanisms of hepatic stellate cell activation[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(7): 397-411. DOI: 10.1038/nrgastro.2017.38.
[4]	GALLUZZI L, BAEHRECKE EH, BALLABIO A, et al. Molecular definitions of autophagy and related processes[J]. EMBO J, 2017, 36(13): 1811-1836. DOI: 10.15252/embj.201796697.
[5]	DIKIC I, ELAZAR Z. Mechanism and medical implications of mammalian autophagy[J]. Nat Rev Mol Cell Biol, 2018, 19(6): 349-364. DOI: 10.1038/s41580-018-0003-4.
[6]	ASHFORD TP, PORTER KR. Cytoplasmic components in hepatic cell lysosomes[J]. J Cell Biol, 1962, 12(1): 198-202. DOI: 10.1083/jcb.12.1.198.
[7]	de DUVE C, WATTIAUX R. Functions of lysosomes[J]. Annu Rev Physiol, 1966, 28: 435-492. DOI: 10.1146/annurev.ph.28.030166.002251.
[8]	LOOS B, ENGELBRECHT AM, LOCKSHIN RA, et al. The variability of autophagy and cell death susceptibility: Unanswered questions[J]. Autophagy, 2013, 9(9): 1270-1285. DOI: 10.4161/auto.25560.
[9]	YANG Z, HUANG J, GENG J, et al. Atg22 recycles amino acids to link the degradative and recycling functions of autophagy[J]. Mol Biol Cell, 2006, 17(12): 5094-5104. DOI: 10.1091/mbc.e06-06-0479.
[10]	XIE Z, KLIONSKY DJ. Autophagosome formation: Core machinery and adaptations[J]. Nat Cell Biol, 2007, 9(10): 1102-1109. DOI: 10.1038/ncb1007-1102.
[11]	MIZUSHIMA N, LEVINE B, CUERVO AM, et al. Autophagy fights disease through cellular self-digestion[J]. Nature, 2008, 451(7182): 1069-1075. DOI: 10.1038/nature06639.
[12]	ARIAS E, CUERVO AM. Chaperone-mediated autophagy in protein quality control[J]. Curr Opin Cell Biol, 2011, 23(2): 184-189. DOI: 10.1016/j.ceb.2010.10.009.
[13]	von MUHLINEN N, AKUTSU M, RAVENHILL BJ, et al. LC3C, bound selectively by a noncanonical LIR motif in NDP52, is required for antibacterial autophagy[J]. Mol Cell, 2012, 48(3): 329-342. DOI: 10.1016/j.molcel.2012.08.024.
[14]	QIN ZH, LE WD. Autophagy: Biology and disease[M]. Beijing: Science Press, 2011: 77-87. 秦正红, 乐卫东. 自噬: 生物学与疾病[M]. 北京: 科学出版社, 2011: 77-87.
[15]	WANG WL, MAO YC, ZHU YZ. Research progress of autophagy in viral pneumonia[J]. Chin J Clin Pharmacol Ther, 2020, 25(11): 1315-1320. DOI: 10.12092/j.issn.1009-2501.2020.11.013. 王纬璐, 茅以诚, 朱依谆. 自噬在病毒性肺炎中的研究进展[J]. 中国临床药理学与治疗学, 2020, 25(11): 1315-1320. DOI: 10.12092/j.issn.1009-2501.2020.11.013.
[16]	LYU MJ, MA XD, REN L. Effect of acupuncture combined with medicine-induced autophagy on cognitive function of mice with ApoE gene knockout[J]. J Jilin Univ(Med Edit), 2020, 46(6): 1124-1130, 1345-1346. DOI: 10.13481/j.1671-587x.20200603. 吕美娟, 马贤德, 任路. 针药并用诱导自噬对ApoE基因敲除小鼠认知功能的影响[J]. 吉林大学学报(医学版), 2020, 6(6): 1124-1130, 1345-1346. DOI: 10.13481/j.1671-587x.20200603.
[17]	UENO T, KOMATSU M. Autophagy in the liver: Functions in health and disease[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(3): 170-184. DOI: 10.1038/nrgastro.2016.185.
[18]	ZHOU WC, ZHANG QB, QIAO L. Pathogenesis of liver cirrhosis[J]. World J Gastroenterol, 2014, 20(23): 7312-7324. DOI: 10.3748/wjg.v20.i23.7312.
[19]	ZHOU B, LING L, ZHANG F, et al. Fibronectin type Ⅲ domain-containing 5 attenuates liver fibrosis via inhibition of hepatic stellate cell activation[J]. Cell Physiol Biochem, 2018, 48(1): 227-236. DOI: 10.1159/000491722.
[20]	HIRABARU M, MOCHIZUKI K, TAKATSUKI M, et al. Expression of alpha smooth muscle actin in living donor liver transplant recipients[J]. World J Gastroenterol, 2014, 20(22): 7067-7074. DOI: 10.3748/wjg.v20.i22.7067.
[21]	THOEN LF, GUIMARÃES EL, DOLLÉ L, et al. A role for autophagy during hepatic stellate cell activation[J]. J Hepatol, 2011, 55(6): 1353-1360. DOI: 10.1016/j.jhep.2011.07.010.
[22]	HONG Y, LI S, WANG J, et al. Author Correction: In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A[J]. Sci Rep, 2018, 8(1): 14569. DOI: 10.1038/s41598-018-32560-6.
[23]	CHEN Y, AZAD MB, GIBSON SB. Methods for detecting autophagy and determining autophagy-induced cell death[J]. Can J Physiol Pharmacol, 2010, 88(3): 285-295. DOI: 10.1139/Y10-010.
[24]	HERNÁNDEZ-GEA V, GHIASSI-NEJAD Z, ROZENFELD R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues[J]. Gastroenterology, 2012, 142(4): 938-946. DOI: 10.1053/j.gastro.2011.12.044.
[25]	HERNÁNDEZ-GEA V, HILSCHER M, ROZENFELD R, et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy[J]. J Hepatol, 2013, 59(1): 98-104. DOI: 10.1016/j.jhep.2013.02.016.
[26]	THOEN LF, GUIMARÃES EL, DOLLÉ L, et al. A role for autophagy during hepatic stellate cell activation[J]. J Hepatol, 2011, 55(6): 1353-1360. DOI: 10.1016/j.jhep.2011.07.010.
[27]	CHU Z, WITTE DP, QI X. Saposin C-LBPA interaction in late-endosomes/lysosomes[J]. Exp Cell Res, 2005, 303(2): 300-307. DOI: 10.1016/j.yexcr.2004.09.029.
[28]	LIU J. Mechanism of Hif-1 target gene Bnip3 regulating autophagy and activation of hepatic stellate cells[D]. Wuhan: Huazhong University of Science and Technology, 2019. 刘洁. Hif-1靶基因Bnip3在肝星状细胞活化中调控自噬机制的研究[D]. 武汉: 华中科技大学, 2019.
[29]	HAZARI Y, BRAVO-SAN PEDRO JM, HETZ C, et al. Autophagy in hepatic adaptation to stress[J]. J Hepatol, 2020, 72(1): 183-196. DOI: 10.1016/j.jhep.2019.08.026.
[30]	BOUCHARD MJ, WANG L, SCHNEIDER RJ. Activation of focal adhesion kinase by hepatitis B virus HBx protein: Multiple functions in viral replication[J]. J Virol, 2006, 80(9): 4406-4414. DOI: 10.1128/JVI.80.9.4406-4414.2006.
[31]	WOBSER H, DORN C, WEISS TS, et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells[J]. Cell Res, 2009, 19(8): 996-1005. DOI: 10.1038/cr.2009.73.
[32]	BECHMANN LP, HANNIVOORT RA, GERKEN G, et al. The interaction of hepatic lipid and glucose metabolism in liver diseases[J]. J Hepatol, 2012, 56(4): 952-964. DOI: 10.1016/j.jhep.2011.08.025.
[33]	DING WX, MANLEY S, NI HM. The emerging role of autophagy in alcoholic liver disease[J]. Exp Biol Med (Maywood), 2011, 236(5): 546-556. DOI: 10.1258/ebm.2011.010360.
[34]	NI HM, BOCKUS A, BOGGESS N, et al. Activation of autophagy protects against acetaminophen-induced hepatotoxicity[J]. Hepatology, 2012, 55(1): 222-232. DOI: 10.1002/hep.24690.
[35]	SCHOLTEN D, OSTERREICHER CH, SCHOLTEN A, et al. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice[J]. Gastroenterology, 2010, 139(3): 987-998. DOI: 10.1053/j.gastro.2010.05.005.
[36]	KAUSHAL S, ANNAMALI M, BLOMENKAMP K, et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model[J]. Exp Biol Med (Maywood), 2010, 235(6): 700-709. DOI: 10.1258/ebm.2010.009297.
[37]	HIDVEGI T, EWING M, HALE P, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis[J]. Science, 2010, 329(5988): 229-232. DOI: 10.1126/science.1190354.
[38]	NI Y, LI JM, LIU MK, et al. Pathological process of liver sinusoidal endothelial cells in liver diseases[J]. World J Gastroenterol, 2017, 23(43): 7666-7677. DOI: 10.3748/wjg.v23.i43.7666.
[39]	MARETTI-MIRA AC, WANG X, WANG L, et al. Incomplete differentiation of engrafted bone marrow endothelial progenitor cells initiates hepatic fibrosis in the rat[J]. Hepatology, 2019, 69(3): 1259-1272. DOI: 10.1002/hep.30227.
[40]	RUART M, CHAVARRIA L, CAMPRECIÓS G, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury[J]. J Hepatol, 2019, 70(3): 458-469. DOI: 10.1016/j.jhep.2018.10.015.
[41]	HAMMOUTENE A, BIQUARD L, LASSELIN J, et al. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis[J]. J Hepatol, 2020, 72(3): 528-538. DOI: 10.1016/j.jhep.2019.10.028.
[42]	LUO X, WANG D, ZHU X, et al. Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration[J]. Cell Death Dis, 2018, 9(5): 576. DOI: 10.1038/s41419-018-0567-0.
[43]	GOMEZ PERDIGUERO E, KLAPPROTH K, SCHULZ C, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors[J]. Nature, 2015, 518(7540): 547-551. DOI: 10.1038/nature13989.
[44]	KOYAMA Y, BRENNER DA. Liver inflammation and fibrosis[J]. J Clin Invest, 2017, 127(1): 55-64. DOI: 10.1172/JCI88881.
[45]	LOCATELLI L, CADAMURO M, SPIRLì C, et al. Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis[J]. Hepatology, 2016, 63(3): 965-982. DOI: 10.1002/hep.28382.
[46]	MRIDHA AR, WREE A, ROBERTSON A, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice[J]. J Hepatol, 2017, 66(5): 1037-1046. DOI: 10.1016/j.jhep.2017.01.022.
[47]	ILYAS G, ZHAO E, LIU K, et al. Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β[J]. J Hepatol, 2016, 64(1): 118-127. DOI: 10.1016/j.jhep.2015.08.019.
[48]	LODDER J, DENAËS T, CHOBERT MN, et al. Macrophage autophagy protects against liver fibrosis in mice[J]. Autophagy, 2015, 11(8): 1280-1292. DOI: 10.1080/15548627.2015.1058473.
[49]	TAO Y, QIU T, YAO X, et al. Autophagic-CTSB-inflammasome axis modulates hepatic stellate cells activation in arsenic-induced liver fibrosis[J]. Chemosphere, 2020, 242: 124959. DOI: 10.1016/j.chemosphere.2019.124959.
[50]	SUN K, XU L, JING Y, et al. Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis[J]. Cancer Lett, 2017, 388: 198-207. DOI: 10.1016/j.canlet.2016.12.004.
[51]	CASTILLO EF, DEKONENKO A, ARKO-MENSAH J, et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation[J]. Proc Natl Acad Sci U S A, 2012, 109(46): e3168-e3176. DOI: 10.1073/pnas.1210500109.
[52]	PERAL DE CASTRO C, JONES SA, NÍCHEALLAIGH C, et al. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion[J]. J Immunol, 2012, 189(8): 4144-4153. DOI: 10.4049/jimmunol.1201946.
[53]	CASSIDY LD, YOUNG AR, PÉREZ-MANCERA PA, et al. A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo[J]. Autophagy, 2018, 14(7): 1256-1266. DOI: 10.1080/15548627.2018.1458172.
[54]	ZHAO J, QI YF, YU YR. Research advances in the role of oxidative stress in the development and progression of liver fibrosis[J]. J Clin Hepatol, 2019, 35(9): 2067-2071. DOI: 10.3969/j.issn.1001-5256.2019.09.040. 赵杰, 齐永芬, 鱼艳荣. 氧化应激在肝纤维化发生发展中的作用[J]. 临床肝胆病杂志, 2019, 35(9): 2067-2071. DOI: 10.3969/j.issn.1001-5256.2019.09.040.
[55]	WANG Y, XU KY, BAO JF. Regulation of autophagy on oxidative stress pathwayand its effect on liver fibrosis[J]. Chin J Health Lab Technol, 2020, 30(14): 1716-1718. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ202014016.htm 王莹, 徐渴阳, 包剑锋. 细胞自噬对氧化应激通路的调节及其对肝纤维化的影响[J]. 中国卫生检验杂志, 2020, 30(14): 1716-1718. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ202014016.htm
[56]	LI J, CHEN K, LI S, et al. Protective effect of fucoidan from Fucus vesiculosus on liver fibrosis via the TGF-β1/Smad pathway-mediated inhibition of extracellular matrix and autophagy[J]. Drug Des Devel Ther, 2016, 10: 619-630. DOI: 10.2147/DDDT.S98740.
[57]	PARK M, KIM YH, WOO SY, et al. Tonsil-derived mesenchymal stem cells ameliorate CCl₄-induced liver fibrosis in mice via autophagy activation[J]. Sci Rep, 2015, 5: 8616. DOI: 10.1038/srep08616.
[58]	LI J, ZENG C, ZHENG B, et al. HMGB1-induced autophagy facilitates hepatic stellate cells activation: A new pathway in liver fibrosis[J]. Clin Sci (Lond), 2018, 132(15): 1645-1667. DOI: 10.1042/CS20180177.
[59]	HUANG Q, LI JT, LIU YG, et al. Regulatory effectof mTOR pathway-mediated autophagy in liver injury[J]. J Clin Hepatol, 2020, 36(11): 2621-2625. DOI: 10.3969/j.issn.1001-5256.2020.11.051. 黄倩, 李京涛, 刘永刚, 等. mTOR相关信号通路介导的自噬对肝损伤的调控作用[J]. 临床肝胆病杂志, 2020, 36(11): 2621-2625. DOI: 10.3969/j.issn.1001-5256.2020.11.051.
[60]	GAO J, WEI B, de ASSUNCAO TM, et al. Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis[J]. J Hepatol, 2020, 73(5): 1144-1154. DOI: 10.1016/j.jhep.2020.04.044.