Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

Graf, Allyson; Meng, Fanyin; Hargrove, Laura; Kennedy, Lindsey; Han, Yuyan; Francis, Taylor; Hodges, Kyle; Ueno, Yoshiyuki; Nguyen, Quoc-Tuan; Greene, John F.; Francis, Heather

doi:10.1152/ajpgi.00188.2014

Cited by 23 publications

(66 citation statements)

References 53 publications

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“…Antibodies for immunohistochemistry (IHC) and immunofluorescence (IF) were purchased from Abcam (Cambridge, MA). HA enzymatic immunoassay (EIA) kits were purchased from Cayman Chemical (Ann Arbor, MI) …”

Section: Methodsmentioning

confidence: 99%

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

et al. 2017

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Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL) increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC deficient mice. Methods: WT and KitW-sh mice were subjected to sham or BDL for up to 7 days and KitW-sh mice were injected with cultured mast cells or 1X PBS before collecting serum, liver blocks and cholangiocytes. Liver damage was assessed by H&E and ALT levels. IBDM was detected by CK-19 expression and proliferation by Ki-67 immunohistochemistry. Fibrosis was detected by immunohistochemistry, hydroxyproline content and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and TGF-β1 expression/secretion were evaluated. HDC and histamine receptor (HR) expression were detected by qPCR and HA secretion by EIA. To evaluate vascular cells, Von Willebrand (vWF) and VEGF-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and α-SMA measured. Results: BDL-induced liver damage was reduced in the BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL KitW-sh mice, IBDM, proliferation, HSC activation/fibrosis and TGF-β1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW-sh mice. vWF and VEGF-C expression decreased in BDL KitW-sh mice. In KitW-sh mice injected with MCs, IBDM, proliferation, fibrosis and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW-sh mice. Conclusion: MCs promote hyperplasia, fibrosis and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies.

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Section: Methodsmentioning

confidence: 99%

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

et al. 2017

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“…Animals were maintained in micro-isolator cages in a temperature-controlled environment with 12:12-hr light-dark cycles; all animals were fed ad libitum a standard chow diet with free access to drinking water. Studies were performed in 12 wk-old male miR-21 −/− and Mdr2 −/− mice (25–30 gm) and the corresponding WT mice that were subjected to sham or bile duct ligation (BDL) for 1 wk 16, 29 . Liver tissue samples and blocks (paraffin and frozen), serum, cholangiocytes, and cholangiocyte supernatants (after incubation at 37°C for 4 hr) were collected as described 2, 29 .…”

Section: Methodsmentioning

confidence: 99%

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Kennedy

Meng

Venter

et al. 2016

Laboratory Investigation

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Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to play a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR21−/− mice underwent sham or bile duct ligation (BDL) for 1 wk, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and Smad-7 expression. In vitro, immortalized murine biliary cell lines (IMCL) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. Also, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers TGF-β1 and α-SMA. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared to control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.

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“…During BDL, cholangiocytes extensively proliferate and biliary hyperplasia is observed in rodent livers [24–26]. However, only large cholangiocytes proliferate during BDL.…”

Section: Cholangiocyte Heterogeneitymentioning

confidence: 99%

Mechanisms of cholangiocyte responses to injury

Sato

Meng²,

Giang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

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Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

Cited by 23 publications

References 53 publications

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Mechanisms of cholangiocyte responses to injury

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