Jiangxi Institute of Translational Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, P. R. China.
Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, P. R. China.
Gene Ther. 2023 Apr;30(3-4):278-287. doi: 10.1038/s41434-022-00351-4. Epub 2022 Jul 12.
In recent years, receptor for advanced glycation end-products (RAGE) has been documented to induce liver fibrosis and inflammatory reaction. Further, microarray data analysis of this study predicted high expression of RAGE in non-alcoholic fatty liver disease (NAFLD). However, its specific mechanisms remain to be elucidated. Hence, this study is aimed at investigating the mechanistic insights of RAGE in chronic intermittent hypoxia (CIH)-induced NAFLD. ApoE knockout (ApoE) mice were exposed to CIH to induce NAFLD, and primary hepatocytes were also exposed to CIH to mimic in vitro setting. Accordingly, we found that RAGE and NF-κB were upregulated in the liver tissues of CIH-induced NAFLD mice and CIH-exposed hepatocytes. Depleted RAGE attenuated CIH-induced hepatocyte injury, lipid deposition, and inflammation. The relationship between RAGE and NF-κB was analyzed by in silico analysis and correlation analysis. It was demonstrated that knockdown of RAGE inhibited the NF-кB pathway, thus alleviating CIH-induced disorders in hepatocytes. Moreover, in vivo experiments also verified that depletion of RAGE alleviated CIH-induced NAFLD by inhibiting NF-кB pathway. Collectively, loss of RAGE blocked the NF-кB pathway to alleviate CIH-induced NAFLD, therefore, highlighting a potential hepatoprotective target for treating NAFLD.
近年来，晚期糖基化终产物受体（RAGE）已被证实可诱导肝纤维化和炎症反应。此外，本研究的基因芯片数据分析预测 RAGE 在非酒精性脂肪性肝病（NAFLD）中高表达。然而，其具体机制仍有待阐明。因此，本研究旨在探讨 RAGE 在慢性间歇性低氧（CIH）诱导的 NAFLD 中的作用机制。采用载脂蛋白 E 基因敲除（ApoE）小鼠暴露于 CIH 诱导 NAFLD，原代肝细胞也暴露于 CIH 模拟体外环境。结果发现，CIH 诱导的 NAFLD 小鼠肝组织和 CIH 暴露的肝细胞中 RAGE 和 NF-κB 表达上调。RAGE 耗竭减轻了 CIH 诱导的肝细胞损伤、脂质沉积和炎症。通过计算机分析和相关性分析研究了 RAGE 和 NF-κB 之间的关系。结果表明，RAGE 敲低抑制了 NF-κB 通路，从而减轻了 CIH 诱导的肝细胞紊乱。此外，体内实验也证实，通过抑制 NF-κB 通路，RAGE 耗竭减轻了 CIH 诱导的 NAFLD。综上所述，RAGE 缺失阻断了 NF-κB 通路，从而减轻了 CIH 诱导的 NAFLD，提示 RAGE 可能成为治疗 NAFLD 的潜在肝保护靶标。
