title: What doesn't kill you makes you stronger: how hepatocytes survive prolonged cholestasis.
abstract: The goals of the current study are 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 (NF-kappaB) in protection against bile acid-induced apoptosis. 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, taurochenodeoxycholic acid, and to cytokines. Apoptosis was determined by TUNEL staining, active caspase-3 staining, and by activation of caspase-8, caspase-9, and caspase-3. Limited hepatocyte apoptosis and increased expression of NF-kappaB-regulated anti-apoptotic genes A1 and cIAP2 were detected in cholestatic rat liver specimens. Bcl-2 expression was restricted to bile duct epithelium. In contrast to taurochenodeoxycholic acid and tauroursodeoxycholic acid, GCDCA induced apoptosis in a Fas-associated protein with death domain-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 vitroby upregulating A1 and cIAP2. GCDCA induces apoptosis in a mitochondria-controlled pathway in which caspase-8 is activated in a Fas-associated protein with death domain-independent manner. However, bile acid-induced apoptosis in cholestasis is limited. This could be explained by cytokine-induced activation of NF-kappaB-regulated antiapoptosis genes like A1 and cIAP2.
authors.affiliation: Rice Liver Center Laboratory, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Maher