Selective inhibition of hepatic stellate cell and fibroblast-derived LOXL1 attenuates BDL- and Mdr2-/--induced cholestatic liver fibrosis
Selective inhibition of hepatic stellate cell and fibroblast-derived LOXL1 attenuates BDL- and Mdr2-/--induced cholestatic liver fibrosis
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DOI：
10.1152/ajpgi.00004.2023
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发表时间：
2023-12-24
影响因子：
4.5
通讯作者：
You，Hong
中科院分区：
文献类型：
--
作者：
Yan，Xuzhen;Zhang，Ning;You，Hong
赖氨酸氧化酶样1 （LOXL1）蛋白是一种胺氧化酶，由于其胶原交联和细胞内功能，在细胞外基质重塑中起重要作用。LOXL1在胆汁淤积性肝纤维化中的作用尚不清楚。我们测量了两种小鼠胆汁淤积模型[Mdr2敲除（Mdr2−/−）和胆管结扎（BDL）]中LOXL1的表达。我们使用6血清型腺相关病毒（AAV）介导的靶向LOXL1的肝脏递送（AAV2/6-shLoxl1）来研究靶向LOXL1治疗胆汁淤积性肝纤维化的疗效。采用NIH-3T3小鼠成纤维细胞，体外研究LOXL1的功能及调控机制。与相应的对照组相比，mdr2 - / -和BDL小鼠的LOXL1表达显著上调，主要是在富含胶原的纤维间隔和门静脉区域。AAV2/6-shLoxl1显著降低了mdr2−/−和BDL小鼠的LOXL1水平，主要是在desmin阳性的肝星状细胞（hsc）和成纤维细胞中。在mdr2−/−和BDL小鼠中，LOXL1表达减少的同时，导管反应、炎症和纤维化也减少。此外，在mdr2−/−和BDL小鼠中，loxl1干预减少了desmin阳性区域的ki -67阳性细胞。在体外，LOXL1的过表达通过激活血小板来源的生长因子受体和细胞外信号调节的激酶信号通路，显著促进成纤维细胞增殖。我们的研究结果表明，选择性抑制来自HSC/成纤维细胞的LOXL1可减轻胆汁淤积性肝/胆道纤维化、炎症、导管反应和HSC/成纤维细胞增殖。基于我们的发现，LOXL1可能是胆汁淤积性纤维化的潜在治疗靶点。AAV2/6-shLoxl1选择性抑制HSC/成纤维细胞来源的LOXL1可以减少胶原沉积、HSC/成纤维细胞增殖和胆汁淤积性肝纤维化进展。此外，LOXL1的过表达通过激活PDGFRß/PI3K和ERK信号通路，在体外显著促进HSC/成纤维细胞增殖。
Lysyl oxidase-like 1 (LOXL1) proteins are amine oxidases that play a crucial role in extracellular matrix remodeling due to their collagen cross-linking and intracellular functions. The role of LOXL1 in cholestatic liver fibrosis remains unexplored. We measured LOXL1 expression in two murine models of cholestasis [Mdr2 knockout (Mdr2−/−) and bile duct ligation (BDL)]. We used adeno-associated virus (AAV) serotype 6-mediated hepatic delivery against LOXL1 (AAV2/6-shLoxl1) to investigate the therapeutic efficacy of targeting LOXL1 in cholestatic liver fibrosis. NIH-3T3 murine fibroblasts were used to investigate the function and regulatory mechanisms of LOXL1 in vitro. LOXL1 expression was significantly upregulated inMdr2−/−and BDL mice compared with their corresponding controls, predominantly in collagen-rich fibrous septa and portal areas. AAV2/6-shLoxl1 significantly reduced LOXL1 levels inMdr2−/−and BDL mice, mainly in desmin-positive hepatic stellate cells (HSCs) and fibroblasts. Concomitant with reduced LOXL1 expression, there was reduced ductular reaction, inflammation, and fibrosis in bothMdr2−/−and BDL mice. In addition,Loxl1intervention decreased Ki-67-positive cells in the desmin-positive areas in bothMdr2−/−and BDL mice. Overexpression of LOXL1 significantly promoted fibroblast proliferation by activating the platelet-derived growth factor receptor and extracellular signal-regulated kinase signaling pathways in vitro. Our findings demonstrated that selective inhibition of LOXL1 derived from HSCs/fibroblasts attenuated cholestatic liver/biliary fibrosis, inflammation, ductal reaction, and HSC/fibroblast proliferation. Based on our findings, LOXL1 could be a potential therapeutic target for cholestatic fibrosis.NEW & NOTEWORTHYSelectively, inhibition of HSC/fibroblasts-derived LOXL1 by AAV2/6-shLoxl1 could reduce collagen deposition, HSC/fibroblasts proliferation, and cholestatic liver fibrosis progression. In addition, overexpression of LOXL1 significantly promoted HSC/fibroblast proliferation by activating the PDGFRß/PI3K and ERK signaling pathways in vitro.