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Selected Publication:
Baumann-Durchschein, F.
The Role of the M3-Muscarinic Receptor (M3-R) in Bile Formation and Cholangiopathies
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 94
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- Authors Med Uni Graz:
- Baumann-Durchschein Franziska
- Advisor:
- Fickert Peter
- Heinemann Akos
- Höfler Gerald
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- Abstract:
- Cholangiopathies remain the major black box in modern hepatology since their etiology and pathophysiology are almost enigmatic. Therefore, medical treatment modalities for prototypic cholangiopathies such as primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis of critically ill patients (SSC-CIP), and primary biliary cirrhosis (PBC) are limited in their efficacy and consequently there is a frequent need for liver transplantation in such difficult to treat patients. Since cholangiocytes represent both victims and therapeutic targets in cholangiopathies, physiology of these highly specialized epithelial cells lining up bile ducts is of major interest. Cholangiocytes secretory function and regenerative capacity is regulated by numerous transport proteins, specific receptors for cytokines/chemokines, growth factors, hormones, and neurotransmitters. The muscarine 3 receptor (M3-R) represents the primary cholangiocyte receptor for the afferent parasympathetic innervation. Therefore, 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). Liver function and morphology in aged M3-R-/- mice were compared to respective aged WT controls. For the second aim we compared liver injury in both genotypes in different cholestatic models (3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, lithocholic acid (LCA) feeding and common bile duct ligation (CBDL)); these experimental interventions represent well-characterized preclinical models of cholestatic liver disease. To analyze the possible role of the M3-R as a therapeutic target, we treated 4 weeks-old Mdr2-/- mice, a preclinical model for sclerosing cholangitis, with the M3-R agonist bethanechol for 4 and 8 weeks. Besides we performed hepatic vagotomy in different cholestatic models (DDC-feeding, Mdr2 knockout mice) to determine the effect of the parasympathetic nervous system in general on cholestasis. Our experimental findings show that M3-R-signalling significantly influences bile formation. 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. M3-R-/- and WT littermates show different susceptibility in the used cholestatic mouse models, which highlights the important role of this receptor. Since treatment of Mdr2-/- mice with a M3-R agonist decreases liver injury, M3-R signaling may represent a novel therapeutic target in specific cholangiopathies.