Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease worldwide. Numerous evidence has demonstrated that metabolic reprogramming serves as a hallmark associated with an elevated risk of NAFLD progression. Selenoprotein W (SelW) is an extensively expressed hepatic selenoprotein that plays a crucial role in antioxidant function. Here, we first demonstrated that SelW is a significantly distinct factor in the liver tissue of NAFLD patients through the Gene Expression Omnibus (GEO) database. Additionally, loss of SelW alleviated hepatic steatosis induced by a high-fat diet (HFD), and was accompanied by the regulation of metabolic and inflammatory pathways as verified by transcriptomic analysis. Moreover, co-immunoprecipitation (CO-IP), liquid chromatography-tandem mass spectrometry (LC-MS), laser scanning confocal microscopy (LSCM) and molecular docking analysis were subsequently implemented to identify Pyruvate Kinase M2 (PKM2) as a potential interacting protein of SelW. Meanwhile, SelW modulated PKM2 translocation into the nucleus to trigger transactivation of the HIF-1α, in further mediating mitochondrial apoptosis, eventually resulting in mitochondrial damage, ROS excessive production and mtDNA leakage. Additionally, mito-ROS accumulation induced the activation of the NLRP3 inflammasome-mediated pyroptosis, thereby facilitating extracellular leakage of mtDNA. The escaped mtDNA then evokes the cGAS-STING signaling pathway in macrophage, thus inducing a shift in macrophage phenotype. Together, our results suggest SelW promotes hepatocyte apoptosis and pyroptosis by regulating metabolic reprogramming to activate cGAS/STING signaling of macrophages, thereby exacerbating the progression of NAFLD.

中文翻译：

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硒蛋白W在参与非酒精性脂肪肝进展中的作用


非酒精性脂肪肝病（NAFLD）是一种世界范围内的慢性肝病。大量证据表明，代谢重编程是与 NAFLD 进展风险升高相关的一个标志。硒蛋白 W (SelW) 是一种广泛表达的肝硒蛋白，在抗氧化功能中发挥着至关重要的作用。在这里，我们首先通过基因表达综合（GEO）数据库证明了 SelW 是 NAFLD 患者肝组织中一个显着的独特因子。此外，SelW 的丧失减轻了高脂饮食 (HFD) 引起的肝脏脂肪变性，并伴随着代谢和炎症途径的调节，经转录组分析证实。此外，随后采用免疫共沉淀 (CO-IP)、液相色谱-串联质谱 (LC-MS)、激光扫描共聚焦显微镜 (LSCM) 和分子对接分析来鉴定丙酮酸激酶 M2 (PKM2) 作为潜在的相互作用蛋白的SelW。同时，SelW调节PKM2转入细胞核，触发HIF-1α的反式激活，进一步介导线粒体凋亡，最终导致线粒体损伤、ROS过量产生和mtDNA泄漏。此外，mito-ROS的积累诱导NLRP3炎性体介导的细胞焦亡的激活，从而促进mtDNA的细胞外渗漏。逃逸的 mtDNA 随后会唤起巨噬细胞中的 cGAS-STING 信号通路，从而诱导巨噬细胞表型的转变。总之，我们的结果表明 SelW 通过调节代谢重编程激活巨噬细胞的 cGAS/STING 信号传导来促进肝细胞凋亡和焦亡，从而加剧 NAFLD 的进展。