SREBF2 triggers endoplasmic reticulum stress and Bax dysregulation to promote lipopolysaccharide-induced endothelial cell injury,Cell Biology and Toxicology

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SREBF2 triggers endoplasmic reticulum stress and Bax dysregulation to promote lipopolysaccharide-induced endothelial cell injury
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-03-06 , DOI: 10.1007/s10565-021-09593-1
Gang Dong ₁ , Xiaoquan Huang _{1,

2} , Ling Wu ₁ , Siyu Jiang ₁ , Qintian Tan ₁ , Shiyao Chen _{1,

2,

3}

Affiliation

An increased lipopolysaccharide (LPS) level in patients with cirrhosis induced the dysregulation of sterol regulatory element–binding transcription factor 2 (SREBF2), which participated in the modulation of tumor inflammatory microenvironment. However, the role of SREBF2 in the LPS-induced injury of portal vein endothelium was scarcely reported. This study aimed to investigate the effects of SREBF2 on the LPS-induced injury to endothelial cells (ECs) in vitro and in vivo and explore the underlying mechanism. In this study, we found that LPS increased SREBF2 expression through activating the TLR4/JNK/c-Jun pathway and suppressed UBE2I-mediated SREBF2 sumoylation to enhance its transcriptional activity. The dysregulation of SREBF2 induced ER stress by increasing the intracellular cholesterol level and facilitated Bax expression to cause additional damage to LPS-induced ECs. As a potential intervention, miR590-3p negatively regulated SREBF2 expression and upregulated UBE2I expression by targeting TLR4, thus alleviating LPS-induced injury. These results suggest that LPS-induced SREBF2 triggered ER stress and promoted Bax expression to injure ECs, which was reversed by miR590-3p. The mechanisms of SREBF2 mediated LPS-induced endothelial injury of portal vein, which might be the therapeutic target for PVT development in cirrhosis patients.

Graphical abstract

中文翻译：

SREBF2触发内质网应激和Bax失调促进脂多糖诱导的内皮细胞损伤

肝硬化患者脂多糖 (LPS) 水平升高会导致甾醇调节元件结合转录因子 2 (SREBF2) 的失调，其参与调节肿瘤炎症微环境。然而，SREBF2 在 LPS 诱导的门静脉内皮损伤中的作用鲜有报道。本研究旨在探讨 SREBF2 在体外和体内对 LPS 诱导的内皮细胞 (ECs) 损伤的影响，并探讨其潜在机制。在本研究中，我们发现 LPS 通过激活 TLR4/JNK/c-Jun 通路增加 SREBF2 表达，并抑制 UBE2I 介导的 SREBF2 苏木化以增强其转录活性。SREBF2 的失调通过增加细胞内胆固醇水平诱导 ER 应激，并促进 Bax 表达，从而对 LPS 诱导的 ECs 造成额外的损害。作为一种潜在的干预措施，miR590-3p 通过靶向 TLR4 负调节 SREBF2 表达并上调 UBE2I 表达，从而减轻 LPS 诱导的损伤。这些结果表明，LPS 诱导的 SREBF2 触发了 ER 应激并促进了 Bax 表达以损伤 EC，这被 miR590-3p 逆转。SREBF2介导LPS诱导的门静脉内皮损伤的机制，可能是肝硬化患者PVT发展的治疗靶点。这些结果表明，LPS 诱导的 SREBF2 触发了 ER 应激并促进了 Bax 表达以损伤 EC，这被 miR590-3p 逆转。SREBF2介导LPS诱导的门静脉内皮损伤的机制，可能是肝硬化患者PVT发展的治疗靶点。这些结果表明，LPS 诱导的 SREBF2 触发了 ER 应激并促进了 Bax 表达以损伤 EC，这被 miR590-3p 逆转。SREBF2介导LPS诱导的门静脉内皮损伤的机制，可能是肝硬化患者PVT发展的治疗靶点。

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更新日期：2021-03-07

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