PCTR1 通过促进 FADS1/FASDS2/ELOV2 表达和降低 PLA2 表达来调节亚油酸代谢，从而改善脂多糖诱导的急性炎症和多器官损伤。,Laboratory Investigation

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PCTR1 通过促进 FADS1/FASDS2/ELOV2 表达和降低 PLA2 表达来调节亚油酸代谢，从而改善脂多糖诱导的急性炎症和多器官损伤。
Laboratory Investigation ( IF 5.1 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41374-020-0412-9
Yong-Jian Liu ₁ , Hui Li ₁ , Yang Tian ₁ , Jun Han ₁ , Xin-Yang Wang ₁ , Xin-Yu Li ₁ , Chao Tian ₁ , Pu-Hong Zhang ₁ , Yu Hao ₁ , Fang Gao _{1,

2} , Sheng-Wei Jin ₁

Affiliation

革兰氏阴性细菌感染由于其外膜成分脂多糖 (LPS) 而导致过度炎症反应和急性器官损伤或功能障碍。Protectin conjugates in tissue regeneration 1 (PCTR1) 是一种内源性脂质介质，在感染期间发挥基本的抗炎作用和促消退作用。在本研究中，我们在 LPS 诱导的急性炎症小鼠模型中检测了 PCTR1 对全身炎症反应、器官形态学损伤和功能障碍以及血清代谢生物标志物的特性。结果表明，PCTR1降低了血清炎症因子，改善了肺、肝、肾的形态学损伤和功能障碍，最终提高了LPS诱导的小鼠急性炎症的存活率。此外，代谢组学分析和高效液相色谱-质谱分析表明，LPS 刺激的血清亚油酸 (LA)、花生四烯酸 (AA) 和前列腺素 E2 (PGE2) 水平被 PCTR1 显着改变。此外，PCTR1 上调 LPS 抑制的脂肪酸去饱和酶 1 (FADS1)、脂肪酸去饱和酶 2 (FADS2) 和极长链脂肪酸延长酶 2 (ELOVL2) 的表达，并下调 LPS 刺激的磷脂酶 A2 (PLA2) 的表达以增加AA 的肝内含量。然而，PCTR1 的这些作用被脂氧素 A4 受体 (ALX) 拮抗剂 (BOC-2) 部分消除。总之，通过激活 ALX，PCTR1 通过上调 FADS1、FADS2 和 ELOVL2 表达促进 LA 向 AA 的转化，

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PCTR1 ameliorates lipopolysaccharide-induced acute inflammation and multiple organ damage via regulation of linoleic acid metabolism by promoting FADS1/FASDS2/ELOV2 expression and reducing PLA2 expression.

Gram-negative bacterial infection causes an excessive inflammatory response and acute organ damage or dysfunction due to its outer membrane component, lipopolysaccharide (LPS). Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenous lipid mediator, exerts fundamental anti-inflammation and pro-resolution during infection. In the present study, we examined the properties of PCTR1 on the systemic inflammatory response, organic morphological damage and dysfunction, and serum metabolic biomarkers in an LPS-induced acute inflammatory mouse model. The results show that PCTR1 reduced serum inflammatory factors and ameliorated morphological damage and dysfunction of the lung, liver, kidney, and ultimately improved the survival rate of LPS-induced acute inflammation in mice. In addition, metabolomics analysis and high performance liquid chromatography-mass spectrometry revealed that LPS-stimulated serum linoleic acid (LA), arachidonic acid (AA), and prostaglandin E2 (PGE2) levels were significantly altered by PCTR1. Moreover, PCTR1 upregulated LPS-inhibited fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongase of very long chain fatty acids 2 (ELOVL2) expression, and downregulated LPS-stimulated phospholipase A2 (PLA2) expression to increase the intrahepatic content of AA. However, these effects of PCTR1 were partially abrogated by a lipoxin A4 receptor (ALX) antagonist (BOC-2). In summary, via the activation of ALX, PCTR1 promotes the conversion of LA to AA through upregulation of FADS1, FADS2, and ELOVL2 expression, and inhibits the conversion of bound AA into free AA through downregulation of PLA2 expression to decrease the serum AA and PGE2 levels.

更新日期：2020-04-24

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