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

Abstract

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.

Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet

“…We have previously shown that HSCs express H1HR, ( 10 ) and inhibition of MC activation blocks HSC activation and liver fibrosis in cholestatic models. ( 9,21 ) Furthermore, histamine treatment promotes liver fibrosis and HSC presence ( 32 ) ; however, the direct impact of histamine on HSCs is undefined and requires further work.…”

“…Similarly, previous work has found that loss of histamine synthesis reduces VEGF‐A expression and subsequent angiogenesis in a mouse model of PSC. ( 32 )…”

“…B liver fibrosis and HSC presence (32) ; however, the direct impact of histamine on HSCs is undefined and requires further work.…”

Two Sides of the Coin: Mast Cells as a Key Regulator of Allergy and Acute/Chronic Inflammation

“…Histamine, another substance secreted by MCs, also induces fibrosis. It is reported that histamine stimulates fibroblast proliferation and collagen synthesis [ 91 , 92 ]. Histamine has four receptors: H1R, H2R, H3R and H4R.…”

Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease

“…It is known that small cholangiocytes primarily express H1HR, whereas large cholangiocytes express H2HR, and binding of histamine to H1 or H2 HR promotes biliary proliferation and subsequent liver fibrosis [48,49]. It has been largely demonstrated that loss of histamine signaling or inhibition of H1 or H2 HR is able to ameliorate biliary proliferation and subsequent liver fibrosis in models of cholestasis [50][51][52]. Biliary neuroendocrine phenotype induced in cholestasis and other chronic liver diseases is associated with an atypical ductular reaction and is generally associated with pronounced inflammatory responses and peribiliary fibrosis [46], thus understanding this compartment during NAFLD may be key.…”