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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Durchschein, F; Krones, E; Pollheimer, MJ; Zollner, G; Wagner, M; Raufman, JP; Fickert, P.
Genetic loss of the muscarinic M3 receptor markedly alters bile formation and cholestatic liver injury in mice.
Hepatol Res. 2018; 48(3):E68-E77
Doi: 10.1111/hepr.12928
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- Führende Autor*innen der Med Uni Graz
- Baumann-Durchschein Franziska
- Fickert Peter
- Co-Autor*innen der Med Uni Graz
- Pollheimer Marion
- Tatscher Elisabeth
- Wagner Martin
- Zollner Gernot
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- Abstract:
- Hepatic innervation represents a potentially underestimated regulator of liver function and regeneration. The muscarinic 3 receptor (M3 -R) is the primary cholangiocyte receptor for the afferent parasympathetic innervation of bile ducts. We aimed to determine the specific role of the M3 -R in bile formation and models for cholestatic liver disease in mice. We compared bile flow and composition in M3 -R knock-out mice (M3 -R-/- ) and wild type littermates (WT). Furthermore, we compared liver inury of M3 -R-/- and WT mice after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, a well-characterized preclinical model of cholestatic liver disease. To analyze the possible role of the M3 -R as a therapeutic target, we treated 4-week-old Mdr2-/- mice, a preclinical model for sclerosing cholangitis, with the M3 -R agonist bethanechol for 4 weeks. M3 -R-/- mice showed significantly reduced bile flow compared to WT mice, most likely due to decreased biliary HCO3- secretion. However, even aged M3 -R-/- mice did not spontaneously develop liver injury or cholestasis. Challenging M3 -R-/- and WT littermates with DDC feeding showed substantially aggravated liver injury in M3 -R-/- mice. After 4 weeks bethanechol treatment, Mdr2-/- mice showed less liver injury compared to controls. Our experimental findings suggest that M3 -R-signalling significantly influences bile formation. Loss of the M3 -R increases susceptibility to cholestatic injury in DDC-fed mice. Since treatment of Mdr2-/- mice with a M3 -R agonist decreases liver injury, M3-R signaling may represent a therapeutic target in specific cholangiopathies. © 2017 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.
- Find related publications in this database (Keywords)
- bile flow
- biliary bicarbonate secretion
- cholestatic liver disease
- hepatic nervous system
- muscarinic receptor