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.

Bile acids: regulation of apoptosis by ursodeoxycholic acid

“…In fact, basic cellular mechanisms of hepatocyte injury might be primarily involved, ultimately causing cell death by either necrosis or apoptosis. There are several studies showing association between caspase activation, mitochondrial dysfunction, and cellular distribution of Bcl-2-related proteins in models of cholestasis and hepatocyte injury ( 49 ). Indeed, pathophysiological concentrations of bile acids induce apoptosis both by directly activating death receptors ( 50 ) and inducing oxidative damage and mitochondrial dysfunction ( 51,52 ), a combination that strongly sensitizes cells to apoptosis ( Fig.…”

Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications

“…A strong association exists between hepatocellular apoptosis and cholestasis [20], and accumulated bile acids appear to play a key role [3,21]. Bile-acid-induced apoptosis involves the activation of (i) the intrinsic (mitochondrial) pathway, triggered by the release into the cytosol of pro-apoptotic mitochondrial factors through pores in the mitochondrial membranes, followed by the activation of executioner caspases, (ii) the extrinsic pathway, triggered by the activation of death receptors localized at the plasma membrane, and (iii) apoptosis by ER (endoplasmic reticulum) stress, involving the activation of executioner caspases without the mediation of mitochondrial factors.…”

Role of Nuclear Steroid Receptors in Apoptosis

“…Several studies have shown that caspase activation, mitochondrial dysfunction, and cellular distribution of Bcl-2-related proteins determine the fate of hepatocytes in models of cholestasis [116]. Indeed, pathophysiological concentrations of bile acids induce both ligand-dependent and -independent death receptor pathways and modulate downstream signaling pathways, a combination that strongly sensitizes cells to apoptosis.…”