BACKGROUND AIMS Parenteral nutrition associated cholestasis (PNAC) is 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 STAT6 signaling and hepatic macrophage polarization that would mediate hepatic protection in PNAC. APPROACH 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), Abcb11, Abcg5, Abcg8, Nr0b2 and Abcc2 mRNA, all of which were reduced in PNAC mice. To determine the mechanism of DLPC effect, we performed RNA-sequencing analysis of liver from Chow, DSS-PN and DSS-PN/DLPC mice, which revealed DLPC upregulation of the anti-inflammatory STAT6 pathway. In intrahepatic mononuclear cells 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 LPS 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 LPS, phytosterols or both resulted in enhanced elevation of IL-1B mRNA expression. Furthermore, 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.

中文翻译：

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LRH-1 激动剂 DLPC 通过 STAT6 促进巨噬细胞极化并预防小鼠肠外营养相关的胆汁淤积。

背景 目的 肠外营养相关胆汁淤积 (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 LRH-1 被其激动剂二月桂酰磷脂酰胆碱 (DLPC) 激活，将触发 STAT6 信号传导和肝巨噬细胞极化，从而介导 PNAC 中的肝脏保护。方法结果 PNAC 小鼠模型（口服 DSSx4d，随后 PNx14d；DSS-PN）用 LRH-1 激动剂 DLPC（30 mg/kg/天）静脉注射治疗。DLPC 治疗可预防肝损伤和胆汁淤积，同时诱导 Nr5a2)、Abcb11、Abcg5、Abcg8、Nr0b2 和 Abcc2 mRNA 的肝脏 mRNA 表达，所有这些在 PNAC 小鼠中均减少。为了确定 DLPC 作用的机制，我们对 Chow、DSS-PN 和 DSS-PN/DLPC 小鼠的肝脏进行了 RNA 测序分析，结果揭示了 DLPC 上调抗炎 STAT6 通路。在 PNAC 小鼠的肝内单核细胞中，DLPC 治疗可防止促炎 (M1) 基因的上调，抑制 NFκB 的激活并诱导 STAT6 及其靶基因的磷酸化，表明 M2 巨噬细胞极化。DLPC 与培养巨噬细胞的体外孵育表明，暴露于 LPS 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 LPS、植物甾醇或两者的 THP-1 细胞中，通过 siRNA 抑制 STAT6 表达会导致 IL-1B mRNA 表达升高。此外，STAT6 siRNA 消除了 DLPC 对 THP-1 细胞的保护作用。结论 这些结果表明，DLPC 激活 LRH-1 可以通过 STAT6 介导的巨噬细胞极化来防止 PNAC 肝损伤。