Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l-histidine decarboxylase/histamine signaling

Primary sclerosing cholangitis (PSC) is characterized by biliary damage and fibrosis. Multidrug resistance-2 gene knockout (Mdr2−/−) mice and PSC patients have increased histamine (HA) levels (synthesized by l-histidine decarboxylase, HDC) and HA receptor (HR) expression. Cholestatic HDC−/− mice display ameliorated biliary damage and hepatic fibrosis. The current study evaluated the effects of knockout of HDC−/− in Mdr2−/− mice (DKO) on biliary damage and hepatic fibrosis. WT, Mdr2−/− mice, and homozygous DKO mice were used. Selected DKO mice were treated with HA. We evaluated liver damage along with HDC expression and HA serum levels. Changes in ductular reaction were evaluated along with liver fibrosis, inflammation and bile acid signaling pathways. The expression of H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C was determined. In vitro, cholangiocyte lines were treated with HA with/without H1/H2 inhibitors before measuring: H1/H2HR, TGF-β1, and VEGF-C expression. Knockout of HDC ameliorates hepatic damage, ductular reaction, fibrosis, inflammation, bile acid signaling and H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C signaling. Reactivation of the HDC/HA axis increased these parameters. In vitro, stimulation with HA increased HR expression and PKC-α, TGF-β1, and VEGF-C expression, which was reduced with HR inhibitors. Our data demonstrate the key role for the HDC/HA axis in the management of PSC progression. This study demonstrates that ablation of the l-histidine decarboxylase /histamine axis using a genetically modified mouse model ameliorates liver damage and hepatic fibrosis. Further, histamine reactivates the axis via H1/H2 receptors, thus recapitulating the liver damage and fibrosis of primary sclerosing cholangitis. Histamine regulation of TGF-β1 and VEGF-C may be targeted therapies for this disease.