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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 35 Issue 3
Mar.  2019
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Article Contents

Mechanism of the activation of hepatic stellate cells:An exploration of new diagnostic markers and therapeutic targets for liver fibrosis

DOI: 10.3969/j.issn.1001-5256.2019.03.042
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  • Received Date: 2018-08-30
  • Published Date: 2019-03-20
  • Liver fibrosis has a complex pathogenesis, and at present, the research mainly focuses on hepatic stellate cells ( HSC) . Many stim-ulating factors and regulatory pathways have been found to promote the activation of HSC. This article reviews the recent research findings onseveral major cytokines and peroxisome proliferator-activated receptor γ and research hotspots in recent years, including the association of mi-croRNAs, long non-coding RNA, and exosomes with HSC activation. This article also introduces potential targets for the treatment of liver fi-brosis and new markers for noninvasive diagnosis of liver diseases and proposes that chemical drugs or traditional Chinese medicine compoundswhich act on the targets of HSC activation can be formulated, in order to make a breakthrough in the therapeutics of liver fibrosis.

     

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  • [1] CARSON JP, RAMM GA, ROBINSON MW, et al. Schistosome-induced fibrotic disease:The role of hepatic stellate cells[J]. Trends Parasitol, 2018, 34 (6) :524-540.
    [2] JUNG YK, YIM HJ. Reversal of liver cirrhosis:current evidenceand expectations[J]. Korean J Intern Med, 2017, 32 (2) :213-228.
    [3] TSUCHIDA T, FRIEDMAN SL. Mechanisms of hepatic stellatecell activation[J]. Nat Rev Gastroenterol Hepatol, 2017, 14 (7) :397-411.
    [4] WAKE K.“Sternzellen”in the liver:Perisinusoidal cells withspecial reference to storage of vitamin A[J]. Am J Anat, 1971, 132 (4) :429-462.
    [5] MEDERACKE I, DAPITO DH, AFFS, et al. High-yield andhigh-purity isolation of hepatic stellate cells from normal andfibrotic mouse livers[J]. Nat Protoc, 2015, 10 (2) :305-315.
    [6] LEE YA, WALLACE MC, FRIEDMAN SL. Pathobiology of liverfibrosis:A translational success story[J]. Gut, 2015, 64 (5) :830-841.
    [7] UENO T, SATA M, SAKATA R, et al. Hepatic stellate cellsand intralobular innervation in human liver cirrhosis[J]. HumPathol, 1997, 28 (8) :953-959.
    [8] HIGASHI T, FRIEDMAN SL, HOSHIDA Y. Hepatic stellate cells askey target in liver fibrosis[J]. Adv Drug Deliv Rev, 2017, 121:27-42.
    [9] KATZ LH, LIKHTER M, JOGUNOORI W, et al. TGFβsignalingin liver and gastrointestinal cancers[J]. Cancer Lett, 2016, 379 (2) :166-172.
    [10] LILIANA A, JEFFREY LW. Smads as transcriptional co-mod-ulators[J]. Curr Opin Cell Biol, 2000, 12 (2) :235-243.
    [11] CHEN J, KATZ LH, MUNOZ NM, et al. Vitamin D deficiencypromotes liver tumor growth in transforming growth factor-be-ta/Smad3-deficient mice through Wnt and Toll-like receptor7 pathway modulation[J]. Sci Rep, 2016, 6:30217.
    [12] LI XF, CHEN H, YI ZJ, et al. Imidazoline I2 receptor inhibitoridazoxan regulates the progression of hepatic fibrosis via AktNrf2 Smad2/3 signaling pathway[J]. Oncotarget, 2017, 8 (13) :21015-21030.
    [13] LI HY, JU D, ZHANG DW, et al. Activation of TGF-beta1-CD147 positive feedback loop in hepatic stellate cells pro-motes liver fibrosis[J]. Sci Rep, 2015, 5:16552.
    [14] CAI X, LI Z, ZHANG Q, et al. CXCL6-EGFR-inducedKupffer cells secrete TGF-beta1 promoting hepatic stellatecell activation via the SMAD2/BRD4/C-MYC/EZH2 pathwayin liver fibrosis[J]. J Cell Mol Med, 2018, 22 (10) :5050-5061.
    [15] ROSKOSKI R. The role of small molecule platelet-derived growthfactor receptor (PDGFR) inhibitors in the treatment of neoplasticdisorders[J]. Pharmacol Res, 2018, 129:65-83.
    [16] DING Q, LI Z, LIU B, et al. Propranolol prevents liver cirrhosisby inhibiting hepatic stellate cell activation mediated by thePDGFR/Akt pathway[J]. Hum Pathol, 2018, 76:37-46.
    [17] KOSTALLARI E, HIRSOVA P, PRASNICKA A, et al. Hepaticstellate cell-derived PDGFR alpha-enriched extracellularvesicles promote liver fibrosis in mice through SHP2[J]. Hep-atology, 2018, 68 (1) :333-348.
    [18] YANG L, KWON J, POPOV Y, et al. Vascular endothelialgrowth factor promotes fibrosis resolution and repair in mice[J]. Gastroenterology, 2014, 146 (5) :1339-1350. e1.
    [19] PETROSINO JM, LEASK A, ACCORNERO F. Genetic manipu-lation of CCN2/CTGF unveils cell-specific ECM-remodelingeffects in injured skeletal muscle[J]. FASEB J, 2018.[Epubahead of print]
    [20] HUANG G, BRIGSTOCK DR. Regulation of hepatic stellatecells by connective tissue growth factor[J]. Front Biosci, 2015, 17:2495-2507.
    [21] CHEN L, CHEN R, VELAZQUEZ VM, et al. Fibrogenic signa-ling is suppressed in hepatic stellate cells through targeting ofconnective tissue growth factor (CCN2) by cellular or exosom-al microRNA-199a-5p[J]. Am J Pathol, 2016, 186 (11) :2921-2933.
    [22] HAZRA S, XIONG S, WANG J, et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch fromactivated to quiescent hepatic stellate cells[J]. J Biol Chem, 2004, 279 (12) :11392-11401.
    [23] MORAN-SALVADOR E, TITOS E, RIUS B, et al. Cell-specificPPARgamma deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchy-mal liver cells[J]. J Hepatol, 2013, 59 (5) :1045-1053.
    [24] IWAISAKO K, HAIMERL M, PAIK YH, et al. Protection from liv-er fibrosis by a peroxisome proliferator-activated receptordelta agonist[J]. Proc Natl Acad Sci U S A, 2012, 109 (21) :e1369-e1376.
    [25] ZHANG F, LU S, HE J, et al. Ligand activation of PPARγbyligustrazine suppresses pericyte functions of hepatic stellatecells via SMRT-mediated transrepression of HIF-1α[J].Theranostics, 2018, 8 (3) :610-626.
    [26] RATZIU V, HARRISON SA, FRANCQUE S, et al. Elafibranor, an agonist of the peroxi-some proliferator-activated recep-tor-alpha and-delta, induces resolution of nonalcoholicsteatohepatitis without fibrosis worsening[J]. Gastroenterolo-gy, 2016, 150 (5) :1147-1159. e5.
    [27] JIANG XP, AI WB, WAN LY, et al. The roles of microRNAfamilies in hepatic fibrosis[J]. Cell Biosci, 2017, 7:34.
    [28] LI Z, JI L, SU S, et al. Leptin up-regulates microRNA-27a/b-3p level in hepatic stellate cells[J]. Exp Cell Res, 2018, 366 (1) :63-70.
    [29] HU D, HU Y, XU W, et al. miR-203 inhibits the expression ofcollagen-related genes and the proliferation of hepatic stellat-e cells through a SMAD3-dependent mechanism[J]. MolMed Rep, 2017, 16 (2) :1248-1254.
    [30] ZOU Y, CAI Y, LU D, et al. MicroRNA-146a-5p attenuatesliver fibrosis by suppressing profibrogenic effects of TGFβ1and lipopolysaccharide[J]. Cell Signal, 2017, 39:1-8.
    [31] CHEN J, YU Y, LI S. et al. MicroRNA-30a ameliorates he-patic fibrosis by inhibiting Beclin1-mediated autophagy[J].J Cell Mol Med, 2017, 21 (12) :3679-3692.
    [32] ZHENG J, DONG P, MAO Y, et al. lincRNA-p21 inhibits he-patic stellate cell activation and liver fibrogenesis via p21[J].FEBS J, 2015, 282 (24) :4810-4821.
    [33] ZHANG K, HAN X, ZHANG Z, et al. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβand Notchpathways[J]. Nat Commun, 2017, 8 (1) :144.
    [34] WANG R, DING Q, YAQOOB U, et al. Exosome adherenceand internalization by hepatic stellate cells triggers sphingosine1-phosphate-dependent migration[J]. J Biol Chem, 2015, 290 (52) :30684-30696.
    [35] CHARRIER A, CHEN R, CHEN L, et al. Exosomes mediate in-tercellular transfer of pro-fibro-genic connective tissuegrowth factor (CCN2) between hepatic stellate cells, the prin-cipal fibrotic cells in the liver[J]. Surgery, 2014, 156 (3) :548-555.
    [36] CHEN L, CHARRIER A, ZHOU Y, et al. Epigenetic regulationof connective tissue growth factor by MicroRNA-214 deliveryin exosomes from mouse or human hepatic stellate cells[J].Hepatology, 2014, 59 (3) :1118-1129.
    [37] CHEN L, BRIGSTOCK DR. Integrins and heparan sulfate pro-teoglycans on hepatic stellate cells (HSC) are novel receptorsfor HSC-derived exosomes[J]. FEBS Lett, 2016, 590 (23) :4263-4274.
    [38] DEVHARE PB, SASAKI R, SHRIVASTAVA S, et al. Exosome-mediated intercellular communica-tion between hepatitis Cvirus-infected hepatocytes and hepatic stellate cells[J]. JVirol, 2017, 91 (6) :1-14.
    [39] LEE YS, KIM SY, KO E, et al. Exosomes derived from palmit-ic acid-treated hepatocytes induce fibrotic activation of he-patic stellate cells[J]. Sci Rep, 2017, 7 (1) :3710.
    [40] SEO W, EUN HS, KIM SY, et al. Exosome-mediated activa-tion of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by gammadelta T cells in liver fibrosis[J].Hepatology, 2016, 64 (2) :616-631.
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