LBP Protects Hepatocyte Mitochondrial Function Via the PPAR-CYP4A2 Signaling Pathway in a Rat Sepsis Model
LBP Protects Hepatocyte Mitochondrial Function Via the PPAR-CYP4A2 Signaling Pathway in a Rat Sepsis Model
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DOI：
10.1097/shk.0000000000001808
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发表时间：
2021-05
期刊：
影响因子：
3.1
通讯作者：
Zichen Song;Leilei Meng;Zhixian He;Jing Huang;Fang Li;Jing-jing Feng;Zhuoran Jia;Yue Huang;Wei Liu;Anding Liu;H. Fang
中科院分区：
文献类型：
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作者：
Zichen Song;Leilei Meng;Zhixian He;Jing Huang;Fang Li;Jing-jing Feng;Zhuoran Jia;Yue Huang;Wei Liu;Anding Liu;H. Fang
摘要目的：探讨脂多糖结合蛋白(LBP)在代谢中的作用，优化脓毒症的治疗。设计：通过向−/−大鼠和WT大鼠注射脂多糖建立脓毒症模型，观察不同时间(0，1，6，24 h)肝脏的变化。单位：检测肝脏炎症和损伤情况。优化脓毒症治疗。对象：WT大鼠和LBP−/−大鼠。干预：静脉注射脂多糖建立脓毒症模型。实验方法和主要结果：首先，我们用脂多糖诱导WT和LBP−/−大鼠脓毒症。分别于注射脂多糖后1、6、24 h处死大鼠，采集血清和肝脏标本。结果发现，LBP基因的缺失在1h和6h可减轻LBP诱导的肝脏炎症和损伤，在LBP−/−大鼠肝脏内注射LBP后2 4h可见明显的气泡性变性。结果发现，在注射脂多糖后24 h，−/−大鼠肝脏线粒体损伤程度和ROS水平明显高于WT大鼠。根据转录学结果，−/−大鼠损伤的原因可能是过氧化物酶体增殖物激活受体途径。为了进一步研究PPARα在脓毒症中的作用，我们用雷帕霉素抑制mTOR，并检测线粒体损伤和ROS水平。在脂多糖诱导的脓毒症环境下，雷帕霉素可降低−/−大鼠线粒体损伤和ROS水平。抑制PPARα靶基因产物之一的细胞色素P4A2可降低脂多糖诱导的−/−大鼠体内ROS水平。结论：LBP通过LBP-PPARα-CyP4a2信号通路保护肝线粒体免受内毒素损伤。
Supplemental Digital Content is available in the text ABSTRACT Objectives: To explore the role of LPS binding protein (LBP) in metabolism and optimize sepsis treatment. Design: A sepsis model was established by injecting LPS into LBP−/− rats and WT rats and observing changes in the liver over time (0, 1, 6, and 24 h). Setting: Detecting liver inflammation and injury. Optimizing the treatment of sepsis. Subjects: WT rats and LBP−/− rats. Interventions: We established a sepsis model by injecting LPS intravenously. Measurements and main results: First, we induced sepsis in WT and LBP−/− rats with LPS. The rats were sacrificed, and serum and liver samples were collected at 1, 6, and 24 h after LPS injection. We found that the deletion of LBP reduced LPS-induced liver inflammation and injury at 1 and 6 h. Ballooning degeneration was clearly present in LBP−/− rat livers at 24 h after LPS injection. We found that mitochondrial damage and reactive oxygen species (ROS) levels were higher in LBP−/− rat livers than in WT rat livers at 24 h after LPS injection. According to the transcriptomic results, the peroxisome proliferator-activated receptor (PPAR) pathway may be the reason for lesions in LBP−/− rats. To further investigate the function of PPARα in sepsis, we inhibited mTOR with rapamycin and examined mitochondrial injury and ROS levels. The levels of mitochondrial damage and ROS were reduced after LBP−/− rats were pretreated with rapamycin in the context of LPS-induced sepsis. Inhibiting CYP4a2, one of the PPARα-target gene products, reduced the level of LPS-induced ROS in LBP−/− rats. Conclusion: LBP protects hepatic mitochondria against LPS-induced damage via the LBP-PPARα-CYP4a2 signaling pathway.