Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, P.R. China.
Theranostics. 2020 Apr 6;10(12):5290-5304. doi: 10.7150/thno.42658. eCollection 2020.
: Inflammation plays a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Protein tyrosine phosphatase receptor type O truncated isoform (PTPROt) is an integral membrane protein that has been identified in osteoclasts, macrophages, and B lymphocytes. However, its relationship between inflammation and NASH is largely unknown. Herein, we aimed to study the function of PTPROt in NASH progression. : We established a NASH mouse model in wild-type (WT), PTPRO knockout mice by western diet (WD) and methionine-choline-deficient diet (MCD). In addition, MCD-induced NASH model was established in BMT mice. Moreover, we determined the expression of PTPROt in liver macrophages in human subjects without steatosis, with simple steatosis, and with NASH to confirm the relationship between PTPROt and NASH. assays were also performed to study the molecular role of PTPROt in NASH progression. : Human samples and animal model results illustrated that PTPROt is increased in liver macrophages during NASH progression and is positively correlated with the degree of NASH. Our animal model also showed that PTPROt in liver macrophages can enhance the activation of the NF-κB signaling pathway, which induces the transcription of genes involved in the inflammatory response. Moreover, PTPROt promotes the transcription of pro-oxidant genes and inhibits antioxidant and protective genes via increased activation of the NF-κB signaling pathway, thereby causing an increased level of reactive oxygen species (ROS) and damaged mitochondria. This triggers the NLRP3-IL1β axis and causes a heightened inflammatory response. Notably, PTPROt partially limits inflammation and ROS production by promoting mitophagy, which participates in a negative feedback loop in this model. : Our data strongly indicate that PTPROt plays a dual role in inflammation via the NF-κB signaling pathway in liver macrophages during NASH. Further studies are required to explore therapeutic strategies and prevention of this common liver disease through PTPROt.
炎症在非酒精性脂肪性肝炎（NASH）的进展中起着至关重要的作用。蛋白酪氨酸磷酸酶受体 O 截断异构体（PTPROt）是一种完整的膜蛋白，已在破骨细胞、巨噬细胞和 B 淋巴细胞中被鉴定出来。然而，它与 NASH 之间的关系在很大程度上是未知的。在此，我们旨在研究 PTPROt 在 NASH 进展中的作用。
我们通过西方饮食（WD）和蛋氨酸-胆碱缺乏饮食（MCD）建立了野生型（WT）和 PTPRO 敲除小鼠的 NASH 小鼠模型。此外，在 BMT 小鼠中建立了 MCD 诱导的 NASH 模型。此外，我们确定了人类非脂肪性肝病、单纯性脂肪性肝病和 NASH 患者肝巨噬细胞中 PTPROt 的表达，以确认 PTPROt 与 NASH 之间的关系。还进行了测定以研究 PTPROt 在 NASH 进展中的分子作用。
人类样本和动物模型结果表明，PTPROt 在 NASH 进展过程中在肝巨噬细胞中增加，并且与 NASH 的严重程度呈正相关。我们的动物模型还表明，肝巨噬细胞中的 PTPROt 可以增强 NF-κB 信号通路的激活，从而诱导参与炎症反应的基因的转录。此外，PTPROt 通过增加 NF-κB 信号通路的激活来促进促氧化剂基因的转录并抑制抗氧化和保护基因，从而导致活性氧（ROS）水平升高和受损的线粒体。这触发了 NLRP3-IL1β 轴并引起炎症反应加剧。值得注意的是，PTPROt 通过促进参与此模型负反馈环的自噬来部分限制炎症和 ROS 的产生。
我们的数据强烈表明，PTPROt 通过 NF-κB 信号通路在 NASH 期间的肝巨噬细胞中发挥双重作用来调节炎症。需要进一步研究通过 PTPROt 探索治疗策略和预防这种常见肝病的方法。
