title: Regulation of the histamine/VEGF axis by miR-125b during cholestatic liver injury in mice.
abstract: Histamine is formed by the conversion of l-histidine into histamine by histidine decarboxylase (HDC). We have previously shown that inhibition of HDC blocks cholangiocyte proliferation and silencing of HDC decreases vascular endothelial growth factor (VEGF) expression. We hypothesized that increased HDC expression during cholestatic liver injury is mediated by the down-regulation of the specific miRNA miR-125b, 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 α-methyl-dl-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 HDC and VEGF were measured. miRNA profiling was performed in isolated cholangiocytes. In vitro, miR-125b was overexpressed (or inhibited) or HDC was silenced before measuring HDC and VEGF-A/C expression and cholangiocyte proliferation. After BDL plus α-methyl-dl-histidine, expression of intrahepatic bile duct mass, proliferating cellular nuclear antigen, VEGF-A/C, and HDC 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 HDC both decreased HDC and VEGF expression and cholangiocyte proliferation. Manipulation of miR-125b-regulated HDC/VEGF expression may, thus, be a therapeutic approach for the treatment of aberrant cholangiocyte growth in biliary disorders.
authors.affiliation: Department of Research, Central Texas Veteran's Health Care System, Temple, Texas; Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, Temple, Texas.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza, University of Rome, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Hargrove
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, Temple, Texas.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kennedy
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas.
authors.forename: Allyson
authors.initials: A
authors.lastname: Graf
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas.
authors.forename: Kyle
authors.initials: K
authors.lastname: Hodges
authors.affiliation: CREST, Japan Science and Technology Agency, Yamagata, Japan; Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas.
authors.forename: Taylor
authors.initials: T
authors.lastname: Francis
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza, University of Rome, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Department of Research, Central Texas Veteran's Health Care System, Temple, Texas; Scott and White Digestive Disease Research Center, Scott and White Healthcare, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, Temple, Texas. Electronic address: hfrancis@medicine.tamhsc.edu.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Francis
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002779:Cholestasis / Q000473:pathology*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine