Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
Cytokine. 2018 Jul;107:74-78. doi: 10.1016/j.cyto.2017.11.018. Epub 2017 Dec 6.
Up-regulation of nerve growth factor (NGF) in parenchymal hepatocytes with cholestatic injury has been previously demonstrated to exert hepatoprotective effects in an autocrine manner; however, the overall impact of NGF up-regulation remains elusive. This study aimed to profile the effects of exogenous NGF on cultured primary rat hepatocytes using transcriptome analysis. Total RNA was isolated from hepatocytes with and without 24 h of NGF exposure, and subjected to RNA enrichment by PCR and RNA sequencing procedures. Comparison of transcriptome profiles between control and NGF-stimulated hepatocytes demonstrated that NGF significantly up-regulated 10 genes and down-regulated 23 genes in hepatocytes. Subsequent KEGG pathway enrichment analysis indicated that NGF significantly affected the retinol metabolism pathway via increased retinol dehydrogenase 16 (RDH16) expression. In a mouse model of bile duct ligation-induced cholestatic liver injury, NGF supplementation significantly enhanced RDH16 expression, whereas administration of anti-NGF neutralizing antibodies prominently decreased RDH16 expression in cholestatic livers, supporting the positive role of NGF in the regulation of RDH16 in diseased livers. In vitro study further demonstrated that NGF triggered de novo synthesis of RDH16 in primary rat hepatocytes, mainly through an NF-κB signaling pathway. In conclusion, this study demonstrates the up-regulation of RDH16 by NGF in cultured rat hepatocytes and mouse cholestatic livers, and provides novel insights on the mechanistic role of NGF in the retinol metabolism of livers.
先前的研究表明，在胆汁淤积性损伤的实质肝细胞中，神经生长因子（NGF）的上调以自分泌的方式发挥肝保护作用；然而，NGF 上调的总体影响仍不清楚。本研究旨在通过转录组分析来描述外源性 NGF 对培养的原代大鼠肝细胞的影响。从暴露于 NGF 24 小时的和未暴露于 NGF 的肝细胞中分离总 RNA，并通过 PCR 和 RNA 测序程序进行 RNA 富集。对照和 NGF 刺激的肝细胞转录组图谱的比较表明，NGF 显著上调了肝细胞中的 10 个基因，下调了 23 个基因。随后的 KEGG 途径富集分析表明，NGF 通过增加视黄醇脱氢酶 16（RDH16）的表达，显著影响视黄醇代谢途径。在胆管结扎诱导的胆汁淤积性肝损伤的小鼠模型中，NGF 补充显著增强了 RDH16 的表达，而抗 NGF 中和抗体的给药则明显降低了胆汁淤积性肝中的 RDH16 表达，支持了 NGF 在调节病变肝脏中 RDH16 表达中的积极作用。体外研究进一步表明，NGF 触发了原代大鼠肝细胞中 RDH16 的从头合成，主要通过 NF-κB 信号通路。总之，本研究证明了 NGF 在培养的大鼠肝细胞和小鼠胆汁淤积性肝脏中上调 RDH16，并为 NGF 在肝脏视黄醇代谢中的作用机制提供了新的见解。
