Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Baghdasaryan, A.
Role of Ligand-activated Nuclear Receptors in the Pathogenesis and Treatment of Sclerosing Cholangitis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2012. pp.114.
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- Autor*innen der Med Uni Graz:
- Baghdasaryan Anna
- Betreuer*innen:
- Höfler Gerald
- Malle Ernst
- Trauner Michael
- Altmetrics:
- Abstract:
- Chronic cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic cholestatic liver diseases with limited therapeutic options. Without efficient treatment, cholangiopathies progress rapidly, leading to the liver failure and need for liver transplantation. Although two thirds of PBC patients show biochemical response after standard therapy with ursodeoxycholic acid, treatment in PSC is inefficient at recommended dose and is associated with increased risk of serious adverse effects at higher dose. Thus, there is an urgent need for novel and efficient pharmaceutical therapy in chronic cholangiopathies, especially in PSC. Since cholestasis is associated with inflammation, fibrosis and increased systemic and intrahepatic bile acid (BA) concentrations, targeting molecular mechanisms regulating inflammation and BA homeostasis may be beneficial to treat sclerosing cholangitis. Nuclear receptors play a critical role in inflammation, fibrogenesis and bile homeostasis. Peroxisome-activated receptor gamma (PPAR¿) has anti-inflammatory effects through inhibition of NF-kB signaling pathway and may inhibit pro-fibrogenic cell activation. Nuclear BA receptor farnesoid X receptor (FXR) regulates BA homeostasis, bile secretion and inflammation, whereas membrane-bound G-protein coupled BA receptor TGR5 may induce protective mechanisms by cAMP-mediated bicarbonate production and inhibiting inflammation in Kupffer cells. Therefore, the overall aim of this thesis was to explore the hypothesis that activation of PPAR¿ or the BA receptors FXR and TGR5 may play a critical role in the pathogenesis and treatment of sclerosing cholangitis. In the first part of thesis we hypothesized that PPAR¿ natural agonist curcumin may be beneficial in sclerosing cholangitis via inhibition of activated cholangiocyte phenotype as well as pro-fibrogenic cell activation. Curcumin decreased portal inflammation and biliary fibrosis in the Mdr2-/- model of sclerosing cholangitis by targeting the main cellular events in cholangiopathies: in cholangiocytes curcumin inhibited reactive cholangiocyte phenotype and portal inflammation through PPAR¿-mediated inhibition of chemoattractant molecule production, whereas inhibition of main pro-fibrogenic cell (portal myofibroblast) proliferation was ERK1/2-mediated. In the second part of thesis we hypothesized that FXR activation may decrease portal inflammation via reduction of intrahepatic and systemic concentrations of potentially toxic BAs and/or direct anti-inflammatory effects in hepatocytes, macrophages and cholangiocytes. In addition, TGR5 activation in cholangiocytes may be beneficial through cAMP-mediated stimulation of bile flow and biliary bicarbonate secretion as well as via direct anti-inflammatory effects in Kupffer cells and cholangiocytes. The role of FXR and TGR5 activation was studied in the Mdr2-/- model by using a selective FXR agonist or TGR5 agonists and a dual FXR/TGR5 agonist. Only the dual FXR/TGR5 significantly reduced portal inflammation and biliary fibrosis in Mdr2-/- mice via FXR-mediated promotion of bicarbonate-rich bile secretion (by induction of hepatocellular carbonic anhydrase 14) and simultaneous reduction of biliary BA export (via inhibition of endogenous BA synthesis), thus resulting in the production of less toxic bile. These findings showed for the first time FXR-dependent stimulation of biliary bicarbonate secretion in hepatocytes. Together, this thesis discovered novel cellular and molecular targets for treatment of sclerosing cholangitis. Targeting important signaling mechanisms such as PPAR¿ and ERK1/2 in cholangiocytes and portal myofibroblasts (cell populations involved in portal inflammation and fibrosis) as well as FXR-mediated induction of bicarbonate secretion and modifications of BA homeostasis by hepatocytes provide novel possibilities to treat cholestatic liver diseases such as sclerosing cholangitis in human.