Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice

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.