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Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non
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Background and objectives Liver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF. Design Histological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg , Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl ( Txndc5cKO ) and Alb-Cre;Txndc5fl/fl ( Txndc5Hep-cKO ) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses. Results TXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice. Conclusions ER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF. Data are available on reasonable request. All data are available from the corresponding author on reasonable request.
中文翻译：
背景和目标 肝纤维化 (LF) 发生在慢性肝损伤后。目前，LF 尚无有效的治疗方法。最近，我们确定了含有 5 (TXNDC5) 的硫氧还蛋白结构域，一种 ER 蛋白二硫键异构酶 (PDI)，作为心脏和肺纤维化的关键介质。我们旨在确定 TXNDC5 是否也有助于 LF 及其作为 LF 治疗靶点的潜力。设计 对人肝硬化进行组织学和转录组分析。Col1a1-GFPTg，Alb-Cre；Rosa26-tdTomato 和 Tie2-Cre/ERT2；Rosa26-tdTomato 小鼠用于确定在肝损伤后诱导 TXNDC5 的细胞类型。在人肝星状细胞 (HSC) 中进行了体外研究。Col1a2-Cre/ERT2；Txndc5fl/fl (Txndc5cKO) 和 Alb-Cre；生成 Txndc5fl/fl (Txndc5Hep-cKO) 小鼠以分别删除 HSC 和肝细胞中的 TXNDC5。采用四氯化碳治疗和胆管结扎手术诱导小鼠肝损伤/纤维化。使用组织学、成像和生化分析对 LF 的程度进行量化。结果 TXNDC5 在人和小鼠纤维化肝脏中显着上调，特别是在纤维化病灶处的活化 HSC 中。TXNDC5 是由 HSC 中的转化生长因子 β1 (TGFβ1) 诱导的，它是 HSC 的活化、增殖、存活和细胞外基质产生所必需和充分的。从机制上讲，TGFβ1 通过增加 ER 应激和 ATF6 介导的转录调控来诱导 TXNDC5 表达。此外，TXNDC5 通过其 PDI 活性通过氧化还原依赖性 JNK 和 HSC 中的信号转导和转录激活因子 3 激活促进 LF，激活 HSC 并使它们抵抗细胞凋亡。Txndc5 的 HSC 特异性缺失恢复了小鼠中已建立的 LF。结论 ER蛋白TXNDC5通过氧化还原依赖性HSC活化、增殖和过量的细胞外基质产生促进LF。因此，靶向 TXNDC5 可能是改善 LF 的潜在新治疗策略。可根据合理要求提供数据。所有数据均可根据合理要求从通讯作者处获得。结论 ER蛋白TXNDC5通过氧化还原依赖性HSC活化、增殖和过量的细胞外基质产生促进LF。因此，靶向 TXNDC5 可能是改善 LF 的潜在新治疗策略。可根据合理要求提供数据。所有数据均可根据合理要求从通讯作者处获得。结论 ER蛋白TXNDC5通过氧化还原依赖性HSC活化、增殖和过量的细胞外基质产生促进LF。因此，靶向 TXNDC5 可能是改善 LF 的潜在新治疗策略。可根据合理要求提供数据。所有数据均可根据合理要求从通讯作者处获得。 |
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