Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, P.R. China.
Theranostics. 2020 Jul 23;10(20):9249-9267. doi: 10.7150/thno.46005. eCollection 2020.
Chronic ethanol consumption as a public health problem worldwide boosts the development of chronic liver diseases in hepatitis B virus (HBV)-infected patients. Arachidonic acid metabolite prostaglandin E2 (PGE2) activates regulatory T cells (Tregs) function. Here, we aim to investigate the underlying mechanism by which chronic ethanol consumption enriches the HBV-induced abnormal lipid metabolism and Tregs. The si-RNAs were used to weaken the expression of SWELL1 in HepG2, HepG2.2.15 and K180 cancer cell lines, followed by RNA sequencing from HepG2 cells. Arachidonic acid metabolite PGE2 and LTD4 were measured by ELISA assay and Western blot analysis and RT-qPCR were used to examine HBx and SWELL1 and transcriptional factor Sp1 in clinical HCC samples and cell lines. The effect of chronic ethanol consumption on Tregs was tested by flow cytometry in HBV-Tg mice. The splenic Tregs were collected and analyzed by RNA sequencing. The cooperative effect of ethanol and HBV in abnormal lipid metabolism was observed and . The depression of SWELL1 (or HBx) resulted in the reduction of lipid content and arachidonic acid metabolite, correlating with suppression of relative gene atlas. Ethanol and SWELL1 elevated the levels of PGE2 or LTD4 in the liver of mice and cell lines. Interestingly, the ethanol modulated abnormal lipid metabolism through activating HBx/Sp1/SWELL1/arachidonic acid signaling. Chronic ethanol consumption remarkably increased the population of PBL Tregs and splenic Tregs in HBV-Tg mice, consistently with the enhanced expression of PD-L1 and . Mechanically, RNA-seq data showed that multiple genes were altered in the transcriptomic atlas of Tregs sorting from ethanol-fed mice or HBV-Tg mice. The chronic ethanol intake enriches the HBV-enhanced abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activates Tregs in mice.
慢性乙醇摄入作为全球公共健康问题，促进了乙型肝炎病毒 (HBV) 感染患者慢性肝病的发展。花生四烯酸代谢物前列腺素 E2 (PGE2) 激活调节性 T 细胞 (Tregs) 的功能。在这里，我们旨在研究慢性乙醇摄入通过何种机制丰富 HBV 诱导的异常脂质代谢和 Tregs。使用 siRNA 减弱 HepG2、HepG2.2.15 和 K180 癌细胞系中 SWELL1 的表达，然后对 HepG2 细胞进行 RNA 测序。通过 ELISA 测定和 Western blot 分析测定花生四烯酸代谢物 PGE2 和 LTD4，并在临床 HCC 样本和细胞系中使用 RT-qPCR 检测 HBx 和 SWELL1 以及转录因子 Sp1。通过 HBV-Tg 小鼠中的流式细胞术检测慢性乙醇摄入对 Tregs 的影响。收集脾脏 Tregs 并通过 RNA 测序进行分析。观察到乙醇和 HBV 在异常脂质代谢中的协同作用。SWELL1（或 HBx）的抑制导致脂质含量和花生四烯酸代谢物减少，与相关基因图谱的抑制相关。乙醇和 SWELL1 增加了小鼠和细胞系肝脏中 PGE2 或 LTD4 的水平。有趣的是，乙醇通过激活 HBx/Sp1/SWELL1/花生四烯酸信号来调节异常脂质代谢。慢性乙醇摄入显著增加了 HBV-Tg 小鼠外周血单个核细胞 (PBL) Tregs 和脾脏 Tregs 的数量，与 PD-L1 的增强表达一致。机制上，RNA-seq 数据显示，从乙醇喂养的小鼠或 HBV-Tg 小鼠中分离的 Tregs 的转录组图谱中改变了多个基因。慢性乙醇摄入通过 HBx/SWELL1/花生四烯酸信号丰富了 HBV 增强的异常脂质代谢，并在小鼠中激活了 Tregs。
