Knockout of Histidine Decarboxylase (HDC) Reduces Hepatic Fibrosis in Bile Duct Ligated (BDL) Mice

Abstract

BackgroundHistamine (HA) is formed by the conversion of histidine by histidine decarboxylase (HDC). Cholangiocytes (i) express HDC; (ii) secrete HA; and (iii) proliferate after HA treatment. In cholestatic rodents, there is enhanced biliary hyperplasia and fibrosis.Aimto demonstrate that knockdown of HDC inhibits hepatic fibrosis.MethodsHDC‐/‐ mice along with matching wild‐type (WT) were subjected to sham or bile duct ligation (BDL). Immunohistochemistry was performed for evaluating (i) bile duct mass by CK‐19 and (iii) collagen content by Masson's Trichrome. We measured: (i) serum histamine levels; and (ii) lobular damage, necrosis, inflammation and fibrosis (Sirius Red staining) in liver sections. In cholangiocytes, we studied the expression of a‐SMA, collagen 1, fibronectin and matrix metalloproteinases (MMPs) by qPCR. HA levels were assessed by EIA in serum and cholangiocyte supernatants. In vitro, cholangiocyte cultures were stably transfected with shRNA‐HDC to knockdown HDC expression. After transfection we evaluated: a‐SMA, collagen 1, fibronectin and MMPs by qPCR.ResultsIn BDL HDC‐/‐ mice, there was decreased collagen content, necrosis, inflammation and fibrotic reaction compared to BDL WT mice.imageHA levels were decreased in BDL HDC‐/‐. In BDL HDC‐/‐ cholangiocytes, there was a reduction of a‐SMA, collagen 1, fibronectin and MMP expression compared to BDL WT. In vitro, knockdown of HDC decreased a‐SMA, collagen 1, fibronectin and MMP expression.ConclusionLoss of HDC decreases BDL‐induced hepatic fibrosis. Our data suggests that HDC is a key regulator of the fibrotic reaction seen during cholangiopathies and may be a potential target for treatment.