Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Oxid Med Cell Longev. 2022 May 16;2022:5954437. doi: 10.1155/2022/5954437. eCollection 2022.
PD-L1 is a critical checkpoint that protects tissues from autoimmune injury. Nevertheless, the role of PD-L1 in nonalcoholic fatty liver disease- (NAFLD-) induced liver damage is still unclear. In this study, we examined the role and mechanism of PD-L1 expression on NAFLD-induced liver damage and PD-L1 expression in the livers from patients with NAFLD, and LO2 cells treated by FFA, was significantly increased. FFA triggers a large amount of ROS (generated from NOX4 and damaged mitochondria), promoting the ZNF24 expression and suppressing ZN24 sumoylation, both of which enhance the PD-L1 transcription and expression. The knockdown of PD-L1 increases CD8 + T cells' damage to FFA-treated LO2 cells, while its upregulation limits the liver injury in NAFLD models. Collectively, we demonstrate that FFA promotes PD-L1 expression through the ROS/ZNF24 pathway and suppresses UBE2I-mediated ZNF24 sumoylation to enhance its transcriptional activity of PD-L1. PD-L1 upregulation limits FFA-induced injury of hepatocytes and .
PD-L1 是一个关键的检查点，可保护组织免受自身免疫损伤。然而，PD-L1 在非酒精性脂肪性肝病（NAFLD）引起的肝损伤中的作用尚不清楚。在这项研究中，我们研究了 PD-L1 在 NAFLD 诱导的肝损伤中的作用和机制，以及 PD-L1 在 NAFLD 患者肝脏中的表达。结果发现，游离脂肪酸（FFA）显著增加 LO2 细胞中 PD-L1 的表达。FFA 触发大量 ROS（由 NOX4 和受损线粒体产生），促进 ZNF24 的表达并抑制 ZN24 的 sumoylation，这两者均增强了 PD-L1 的转录和表达。PD-L1 的敲低增加了 CD8+T 细胞对 FFA 处理的 LO2 细胞的损伤，而上调 PD-L1 则限制了 NAFLD 模型中的肝损伤。总之，我们证明了 FFA 通过 ROS/ZNF24 途径促进 PD-L1 的表达，并抑制 UBE2I 介导的 ZNF24 sumoylation，从而增强其 PD-L1 的转录活性。PD-L1 的上调限制了 FFA 诱导的肝细胞损伤。
