Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, No. 324, Jingwuwei 7 Road, Huaiyin District, Jinan, 250021, Shandong Province, People's Republic of China.
Department of Gastroenterology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, People's Republic of China.
Hum Cell. 2022 Nov;35(6):1752-1765. doi: 10.1007/s13577-022-00760-y. Epub 2022 Aug 5.
Lymphocyte antigen 6 family member D (LY6D) was enhanced specifically in senescent cells, while its effects on pyroptosis, a programmed cell death, remains unknown. The goal of this study was to assess the role of LY6D in the mediation of pyroptosis during nonalcoholic steatohepatitis (NASH). After screening out LY6D as a specific liver fibrosis-associated gene using the GSE55747 dataset from the GEO database, we established a NASH mouse model using methionine and choline deficient-diet feeding and an in vitro model using lipopolysaccharide (LPS)-treated hepatocytes. LY6D was overexpressed in NASH livers as well as in LPS-treated hepatocytes. Silencing of LY6D inhibited NASH-associated hepatocyte pyroptosis. With the aid of bioinformatics analysis, promoter-luciferase reporter and ChIP-qPCR assays, we identified FOSL2 as an upstream transcription factor of LY6D. FOSL2, which was highly expressed in NASH, promoted LY6D transcription by binding to the promoter of LY6D. Depletion of FOSL2 significantly inhibited NASH-associated hepatocyte pyroptosis, which was significantly reversed after overexpression of LY6D. Moreover, the promotion of hepatocyte pyroptosis by the FOSL2/LY6D axis was significantly attenuated by specific inhibition of NLRP3. These findings suggesting that FOSL2/LY6D axis may be a key molecular axis and a potential target for NASH therapeutics.
淋巴细胞抗原 6 家族成员 D（LY6D）特异性在衰老细胞中增强，但其对细胞焦亡（一种程序性细胞死亡）的影响尚不清楚。本研究旨在评估 LY6D 在介导非酒精性脂肪性肝炎（NASH）中细胞焦亡中的作用。我们使用 GEO 数据库中的 GSE55747 数据集筛选出 LY6D 作为特定的肝纤维化相关基因后，使用蛋氨酸和胆碱缺乏饮食建立 NASH 小鼠模型，并使用脂多糖（LPS）处理的肝细胞建立体外模型。LY6D 在 NASH 肝脏以及 LPS 处理的肝细胞中过度表达。沉默 LY6D 抑制 NASH 相关的肝细胞细胞焦亡。通过生物信息学分析、启动子-荧光素酶报告和 ChIP-qPCR 实验，我们确定 FOSL2 是 LY6D 的上游转录因子。FOSL2 在 NASH 中高表达，通过与 LY6D 启动子结合促进 LY6D 转录。FOSL2 的耗竭显著抑制 NASH 相关的肝细胞细胞焦亡，而过表达 LY6D 后则显著逆转。此外，FOSL2/LY6D 轴对肝细胞细胞焦亡的促进作用被 NLRP3 的特异性抑制显著减弱。这些发现表明，FOSL2/LY6D 轴可能是 NASH 治疗的关键分子轴和潜在靶点。
