Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice
Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice
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DOI：
10.1016/j.ajpath.2013.11.008
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发表时间：
2014-03-01
影响因子：
6
通讯作者：
Francis, Heather L.
中科院分区：
文献类型：
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作者：
Meng, Fanyin;Onori, Paolo;Francis, Heather L.
组胺是通过组氨酸脱羧酶（HDC）将L-组氨酸转化为组胺而形成的。我们以前已经表明，抑制HOC阻断胆管细胞增殖和沉默HOC降低血管内皮生长因子（VEGF）的表达。我们推测，在胆汁淤积性肝损伤过程中HOC表达的增加是由特定的miRNA miR 125 b（一种转录后调节因子）的下调介导的。对小鼠进行假手术或胆管结扎（BDL），其诱导大胆管细胞增殖，随后用盐水或α-甲基DL-组氨酸（HDC抑制剂）处理7天。获得肝块、血清和大胆管细胞，并测量肝内胆管质量、胆管细胞增殖（增殖细胞核抗原表达）以及HOC和VEGF的表达。在分离的胆管细胞中进行miRNA谱分析。在体外，在测量HOC和VEGF-A/C表达和胆管细胞增殖之前，过表达（或抑制）miR-125 b或沉默HOC。BDL + α-甲基组氨酸组肝内胆管肿块、增殖细胞核抗原、VEGF-A/C、HOC表达及组胺水平均较BDL组降低。BDL后miR-125 b表达显著下调。在体外，过表达miR-125 b和敲低HOC均降低HOC和VEGF表达以及胆管细胞增殖。miR-125 b调控的HOC！因此，VEGF表达可能是治疗胆道疾病中异常胆管细胞生长的治疗方法。
Histamine is formed by the conversion of L-histidine into histamine by histidine decarboxyLase (H DC). We have previously shown that inhibition of HOC blocks cholangiocyte proliferation and silencing of HOC decreases vascular endothelial growth factor (VEGF) expression. We hypothesized that increased HOC expression during cholestatic liver injury is mediated by the down-regulation of the specific miRNA miR125b, a post-transcriptional regulator. Mice were subjected to sham surgery or bile duct Ligation (BDL), which induces Large cholangiocyte proliferation, and subsequently treated with either saline or a-methylDL-histidine (an HDC inhibitor) for 7 days. Liver blocks, serum, and Large cholangiocytes were obtained, and intrahepatic bile duct mass, cholangiocyte proliferation (proliferating cellular nuclear antigen expression), and expression of both HOC and VEGF were measured. miRNA profiling was performed in isolated cholangiocytes. In vitro, miR-125b was overexpressed (or inhibited) or HOC was silenced before measuring HOC and VEGF-A/C expression and cholangiocyte proliferation. After BDL plus a-methyl-ixhistidine, expression of intrahepatic bile duct mass, proliferating cellular nuclear antigen, VEGF-A/C, and HOC and Levels of histamine all decreased compared with those of BDL alone. miR-125b was significantly down-regulated after BDL. In vitro, overexpression of miR-125b and knockdown of HOC both decreased HOC and VEGF expression and cholangiocyte proliferation. Manipulation of miR-125b regulated HOC! VEGF expression may, thus, be a therapeutic approach for the treatment of aberrant cholangiocyte growth in biliary disorders.