Background: progression of chronic cholestatic disorders towards ductopenia results from the dysregulation of cholangiocyte survival, with cell death by apoptosis prevailing over compensatory proliferation. Currently, no therapy is available to sustain cholangiocyte survival in the course of those disorders. We have recently shown that cholangiocytes express the Glucagon-Like Peptide-1 receptor (GLP-1R); its activation results in enhanced proliferative reaction to cholestasis. The GLP-1R selective agonist exendin-4 sustains pancreatic β-cell proliferation and prevents cell death by apoptosis. Exendin-4 is now employed in humans as a novel therapy for diabetes.
Aim: to verify whether exendin-4 is effective in preventing cholangiocyte apoptosis.
Methods: in vitro, we tested if exendin-4 is able to prevent apoptosis of cholangiocytes isolated from normal rats induced by glycochenodeoxycholic acid (GCDCA); in vivo, animals subjected to 1 week bile duct ligation (BDL) and to a single IP injection of CCl4 were treated with exendin-4 for 3 days.
Results: exendin-4 prevented the GCDCA-induced Bax mitochondrial translocation, cytochrome c release and increase in caspase 3 activity. PI3K, but not cAMP/PKA or Ca2+-CamKinase inhibitors neutralized the effects of exendin-4. In vivo, exendin-4 administration prevented the increase in TUNEL positive cholangiocytes and the loss of bile ducts observed in BDL rats treated with CCl4.
Summary/conclusion: exendin-4 prevents cholangiocyte apoptosis both in vitro and in vivo; such an effect is due to the ability of exendin-4 to counteract the activation of the mitochondrial pathway of apoptosis. These findings support the hypothesis that exendin-4 may be effective in relenting the progression of cholangiopathies towards ductopenia.