PDF(Pubmed)
Abstract：
Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P < 0.05 and a fold-change of > |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments.
摘要：
长期接受肠外营养（PN）的肠衰竭患者通常会发展为肠衰竭相关性肝病（IFALD）。虽然有确定的风险因素，早期发病机制了解甚少,治疗选择有限.这里,我们在大型动物IFALD模型中对肝脏组织进行转录组学分析,以产生机制见解并确定治疗靶点.为早产约克郡仔猪提供PN或用母猪奶替代品进行瓶饲喂14天。与奶瓶喂养的控制相比，接受PN治疗的仔猪在生前出现生化胆汁淤积15(总胆红素0.2vs.2.9mg/dL,P=0.01）。进行肝组织的RNA-Seq。独创性通路分析鉴定出747个差异表达基因(343个上调和404个下调),其具有调整的P<0.05和>|1|的倍数变化。确定了丰富的规范途径，显示炎症途径的广泛激活和细胞周期进程的抑制。潜在的治疗方法，包括英夫利昔单抗，糖皮质激素,他汀类药物，和奥贝胆酸被确定为可逆转PN诱导的基因失调的预测上游主调节因子。新生儿IFALD的早期驱动因素可能是肝脏未成熟的炎症；应研究针对肝脏炎症反应的已确定疗法作为潜在治疗方法。
