Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury.
Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury.
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DOI：
10.1136/gutjnl-2015-310752
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发表时间：
2017-06
期刊：
影响因子：
24.5
通讯作者：
Nieto N
中科院分区：
文献类型：
--
作者：
Arriazu E;Ge X;Leung TM;Magdaleno F;Lopategi A;Lu Y;Kitamura N;Urtasun R;Theise N;Antoine DJ;Nieto N
肝纤维化与主要由活化的肝星状细胞(HSCs)产生的大量I型胶原沉积有关；然而，肝细胞损伤和HSC促纤维化反应之间的联系尚不清楚。在这里，我们显示了骨桥蛋白(OPN)和高迁移率族蛋白-1(HMGB1)在肝纤维化中的显著诱导作用。由于OPN被确定为HMGB1的上游，我们推测OPN可能通过增加HMGB1上调I型胶原的表达而参与肝纤维化的发病。长期丙型肝炎病毒(HCV)进展期患者肝脏OPN和HMGB1免疫染色增强，与纤维化分期相关，而非进展期患者的OPN和HMGB1免疫染色增强。与健康外植体相比，丙型肝炎肝纤维化患者肝细胞胞浆OPN和HMGB1表达明显增强，而核HMGB1表达缺失。在注射CCl_4的OpnHep转基因小鼠中，出现了成熟的肝纤维化和明显的HMGB1诱导，但在野生型中较少，在OPN−/−小鼠中几乎没有。肝细胞内HMGB1(HMGB1HEP)对Δ诱导的小鼠肝纤维化有保护作用。与分泌OPN+HMGB1的肝细胞共同培养，并用重组OPN(ROPN)或HMGB1(RHMGB1)攻击，可增强HSCs的I型胶原表达，这种表达可被中和抗体(Abs)和OPN或HMGB1消融所钝化。ROPN通过NADPH氧化酶活性升高和组蛋白脱乙酰酶1/2降低导致I型胶原表达上调，从而诱导HSCs HMGB1乙酰化。最后，rHMGB1通过晚期糖基化终产物受体发出信号，并激活PI3K-pAkt1/2/3途径上调I型胶原。在肝纤维化过程中，OPN的增加诱导HMGB1，HMGB1作为下游的警报蛋白推动HSCs合成I型胶原。
Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression. Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn−/− mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K–pAkt1/2/3 pathway to upregulate collagen-I. During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.
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作者：
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通讯作者：
Nieto, Natalia