BACKGROUND/AIMS: To examine the extent and mechanisms of apoptosis in cholestatic liver injury and to explore the role of the transcription factor nuclear factor-kappa B in protection against bile acid-induced apoptosis. METHODS: Cholestatic liver injury was induced by bile duct ligation in Wistar rats. Furthermore, primary cultures of rat hepatocytes were exposed to glycochenodeoxycholic acid (GCDCA), tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA) and to cytokines. Apoptosis was determined by TUNEL-staining, active caspase-3 staining, activation of caspase-8, -9 and -3. RESULTS: Limited hepatocyte apoptosis and an increased expression of NF-kappaB-regulated anti-apoptotic genes A1 and cIAP2 were detected in cholestatic rat livers. Bcl-2 expression was restricted to bile duct epithelium. In contrast to TCDCA and TUDCA, GCDCA induced apoptosis in a Fas-associated protein with death domain (FADD)-independent pathway in hepatocytes. Although bile acids do not activate NF-kappaB, NF-kappaB activation by cytokines (induced during cholestasis) protected against GCDCA-induced apoptosis in vitro by upregulating A1 and cIAP2. CONCLUSIONS: GCDCA induces apoptosis in a mitochondria-controlled pathway in which caspase-8 is activated in a FADD-independent manner. However, bile acid-induced apoptosis in cholestasis is limited. This could be explained by cytokine-induced activation of NF-kappaB-regulated anti-apoptotic genes like A1 and cIAP2.
BACKGROUND/AIMS: To examine the extent and mechanisms of apoptosis in cholestatic liver injury and to explore the role of the transcription factor nuclear factor-kappa B in protection against bile acid-induced apoptosis. METHODS:Cholestatic liver injury was induced by bile duct ligation in Wistar rats. Furthermore, primary cultures of rat hepatocytes were exposed to glycochenodeoxycholic acid (GCDCA), tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA) and to cytokines. Apoptosis was determined by TUNEL-staining, active caspase-3 staining, activation of caspase-8, -9 and -3. RESULTS: Limited hepatocyte apoptosis and an increased expression of NF-kappaB-regulated anti-apoptotic genes A1 and cIAP2 were detected in cholestaticrat livers. Bcl-2 expression was restricted to bile duct epithelium. In contrast to TCDCA and TUDCA, GCDCA induced apoptosis in a Fas-associated protein with death domain (FADD)-independent pathway in hepatocytes. Although bile acids do not activate NF-kappaB, NF-kappaB activation by cytokines (induced during cholestasis) protected against GCDCA-induced apoptosis in vitro by upregulating A1 and cIAP2. CONCLUSIONS:GCDCA induces apoptosis in a mitochondria-controlled pathway in which caspase-8 is activated in a FADD-independent manner. However, bile acid-induced apoptosis in cholestasis is limited. This could be explained by cytokine-induced activation of NF-kappaB-regulated anti-apoptotic genes like A1 and cIAP2.
Authors: Arndt Vogel; Joseph E Aslan; Holger Willenbring; Christian Klein; Milton Finegold; Howard Mount; Gary Thomas; Markus Grompe Journal: Gastroenterology Date: 2006-01 Impact factor: 22.682
Authors: Chao-Wen Cheng; Caroline C Duwaerts; Nico van Rooijen; Philip Wintermeyer; Stephanie Mott; Stephen H Gregory Journal: J Hepatol Date: 2010-11-18 Impact factor: 25.083
Authors: Benjamin L Woolbright; Daniel J Antoine; Rosalind E Jenkins; Mary Lynn Bajt; B Kevin Park; Hartmut Jaeschke Journal: Toxicol Appl Pharmacol Date: 2013-10-03 Impact factor: 4.219
Authors: Benjamin L Woolbright; Anup Ramachandran; Mitchell R McGill; Hui-min Yan; Mary Lynn Bajt; Matthew R Sharpe; John J Lemasters; Hartmut Jaeschke Journal: Basic Clin Pharmacol Toxicol Date: 2012-09-25 Impact factor: 4.080
Authors: M Marzioni; G Alpini; S Saccomanno; C Candelaresi; J Venter; C Rychlicki; G Fava; H Francis; L Trozzi; A Benedetti Journal: Gut Date: 2008-10-01 Impact factor: 23.059