<br>LRH-1 激动剂 DLPC 通过 STAT6 促进巨噬细胞极化并防止小鼠肠外营养相关的胆汁淤积。,Hepatology

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LRH-1 激动剂 DLPC 通过 STAT6 促进巨噬细胞极化并防止小鼠肠外营养相关的胆汁淤积。
Hepatology ( IF 12.9 ) Pub Date : 2023-11-16 , DOI: 10.1097/hep.0000000000000690
Swati Ghosh ₁ , Michael W Devereaux ₁ , Cuining Liu ₁ , Ronald J Sokol _{1,

2}

Affiliation

背景和目的肠外营养相关胆汁淤积症（PNAC）是 LRH-1 表达降低的肠衰竭患者的重要并发症。在这里，我们假设其激动剂二月桂酰磷脂酰胆碱（DLPC）激活 LRH-1 会触发信号转导和转录激活因子 6 （STAT6）信号传导和肝脏巨噬细胞极化，这将介导 PNAC 中的肝脏保护。方法和结果 PNAC 小鼠模型（口服 DSSx4d 后 PNx14d;DSS-PN）用 LRH-1 激动剂 DLPC （30 mg/kg/d）静脉注射。DLPC 治疗预防了肝损伤和胆汁淤积，同时诱导了肝脏 mRNA 的表达 Nr5a2（核受体亚家族 5 A 组成员 2）、Abcb11（ATP 结合盒亚家族 B 成员 11）、Abcg5（ATP 结合盒 [ABC] 转运蛋白亚家族 G 成员 5）、Abcg8（ATP 结合盒 [ABC] 转运蛋白亚家族 G 成员 8）、核受体亚家族 0 和 ATP 结合盒亚家族 C 成员 2 （Abcc2） mRNA，所有这些在 PNAC 小鼠中均有所降低。为了确定 DLPC 效应的机制，我们对 Chow 、 DSS-PN 和 DSS-PN/DLPC 小鼠的肝脏进行了 RNA 测序分析，揭示了 DLPC 抗炎 STAT6 通路的上调。在 PNAC 小鼠的肝内单核细胞或骨髓来源的巨噬细胞（BMDM）中，DLPC 处理阻止了促炎（M1）基因的上调，抑制了 NFκB 的激活并诱导了 STAT6 及其靶基因的磷酸化，表明 M2 巨噬细胞极化。在体外，DLPC 与培养的巨噬细胞孵育表明，暴露于脂多糖或植物甾醇诱导的 Il-1b 和 Tnf 增加显着减少，这与 STAT6 与其靶基因启动子的结合增加有关。在暴露于脂多糖、植物甾醇或两者的 THP-1 细胞中，siRNA 对 STAT6 表达的抑制导致 IL-1B mRNA 表达升高。此外，STAT6 siRNA 消除了 DLPC 在 THP-1 细胞中的保护作用。结论这些结果表明，DLPC 激活 LRH-1 可能通过 STAT6 介导的巨噬细胞极化防止 PNAC 肝损伤。

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LRH-1 agonist DLPC through STAT6 promotes macrophage polarization and prevents parenteral nutrition-associated cholestasis in mice.

BACKGROUND AND AIMS Parenteral nutrition-associated cholestasis (PNAC) is an important complication in patients with intestinal failure with reduced LRH-1 expression. Here, we hypothesized that LRH-1 activation by its agonist, dilauroylphosphatidylcholine (DLPC), would trigger signal transducer and activator of transcription 6 (STAT6) signaling and hepatic macrophage polarization that would mediate hepatic protection in PNAC. APPROACH AND RESULTS PNAC mouse model (oral DSSx4d followed by PNx14d; DSS-PN) was treated with LRH-1 agonist DLPC (30 mg/kg/day) intravenously. DLPC treatment prevented liver injury and cholestasis while inducing hepatic mRNA expression of Nr5a2 (nuclear receptor subfamily 5 group A member 2), Abcb11 (ATP binding cassette subfamily B member 11), Abcg5 (ATP-binding cassette [ABC] transporters subfamily G member 5), Abcg8 (ATP-binding cassette [ABC] transporters subfamily G member 8), nuclear receptor subfamily 0, and ATP-binding cassette subfamily C member 2 ( Abcc2) mRNA, all of which were reduced in PNAC mice. To determine the mechanism of the DLPC effect, we performed RNA-sequencing analysis of the liver from Chow, DSS-PN, and DSS-PN/DLPC mice, which revealed DLPC upregulation of the anti-inflammatory STAT6 pathway. In intrahepatic mononuclear cells or bone-marrow derived macrophages (BMDM) from PNAC mice, DLPC treatment prevented upregulation of pro-inflammatory (M1) genes, suppressed activation of NFκB and induced phosphorylation of STAT6 and its target genes, indicating M2 macrophage polarization. In vitro, incubation of DLPC with cultured macrophages showed that the increased Il-1b and Tnf induced by exposure to lipopolysaccharides or phytosterols was reduced significantly, which was associated with increased STAT6 binding to promoters of its target genes. Suppression of STAT6 expression by siRNA in THP-1 cells exposed to lipopolysaccharides, phytosterols, or both resulted in enhanced elevation of IL-1B mRNA expression. Furthermore, the protective effect of DLPC in THP-1 cells was abrogated by STAT6 siRNA. CONCLUSIONS These results indicate that activation of LRH-1 by DLPC may protect from PNAC liver injury through STAT6-mediated macrophage polarization.

更新日期：2023-11-17

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