Dong Gang, Huang Xiaoquan, Wu Ling, Jiang Siyu, Tan Qintian, Chen Shiyao
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Center of Evidence-Based Medicine, Fudan University, Shanghai, 200032, People's Republic of China.
Cell Biol Toxicol. 2022 Feb;38(1):185-201. doi: 10.1007/s10565-021-09593-1. Epub 2021 Mar 6.
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. 1. LPS promoted SREBF2 expression by activating the TLR4/JNK/c-Jun pathway and suppressed UBE2I-mediated SREBF2 sumoylation to upregulate SREBF2 transcriptional activity 2. SREBF2-mediated ER stress and Bax expression involved in LPS-induced EC injury 3. miR590-3p decreased SREBF2 expression by targeting TLR4 and mitigated LPS-induced EC injury.
肝硬化患者体内脂多糖（LPS）水平升高会导致固醇调节元件结合转录因子2（SREBF2）失调，后者参与肿瘤炎性微环境的调节。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，并探究其潜在机制。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 SUMO化以增强其转录活性。SREBF2失调通过增加细胞内胆固醇水平诱导内质网应激，并促进Bax表达，从而对LPS诱导的ECs造成额外损伤。作为一种潜在干预措施，miR590-3p通过靶向TLR4负向调节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引发内质网应激并促进Bax表达以损伤ECs，而miR590-3p可逆转这一过程。SREBF2介导LPS诱导的门静脉内皮损伤的机制，可能是肝硬化患者门静脉血栓形成发展的治疗靶点。1. LPS通过激活TLR4/JNK/c-Jun通路促进SREBF2表达，并抑制UBE2I介导的SREBF2 SUMO化以上调SREBF2转录活性 2. SREBF2介导的内质网应激和Bax表达参与LPS诱导的EC损伤 3. miR590-3p通过靶向TLR4降低SREBF2表达并减轻LPS诱导的EC损伤。
