The cirrhotic hepatocyte: navigating between Scylla and Charybdis.

نویسنده

  • Han Moshage
چکیده

In the chronically injured and cholestatic liver, the various hepatic cell types are exposed to a vicious cocktail of toxic and potentially lethal ingredients, such as cytokines, reactive oxygen species (ROS), bile acids, endotoxin and Fas-Ligand expressed on immune cells. Some liver cells thrive in this hostile environment, e.g. stellate cells, which start to proliferate and produce excessive amounts of extracellular matrix and inflammatory and immune cells, which infiltrate the liver and produce cytokines. Others, e.g. hepatocytes, perish in this environment. It is still a matter of debate what the predominant mechanism of hepatocyte cell death is in chronic liver injury: necrosis or apoptosis. This debate is not trivial, because any intervention aimed to protect hepatocytes in the injured liver must be based on a correct understanding of the mechanism of cell death, e.g. apoptosis is a highly regulated process involving numerous steps and components with ample opportunity to intervene and inhibit apoptosis. Prevention of necrosis requires a fundamentally different approach aimed at reducing the necrosis-causing agent. In the chronically injured liver, liver enzymes in serum are elevated. Although increased AST and ALT levels are considered as markers of necrotic cell death, it may result from necrosis secondary to apoptosis (necro-apoptosis) [1]. With the introduction of methods to detect apoptosis, e.g the TUNEL assay, apoptosis was proposed as the major mechanism of cell death in chronic cholestatic liver injury [2]. However, the TUNEL assay appeared to be prone to artifacts. Therefore, more specific methods have been applied, e.g. active caspase-3 staining and morphological criteria. Based on these latter methods, apoptosis as the predominant mode of cell death was questioned and necrosis has been proposed as the major mode of cell death in the cirrhotic liver [3–5]. Bile acids, Fas-Ligand, reactive oxygen species (ROS) and cytokines like TNFa are all potent inducers of apoptotic cell death in normal primary cultures of hepatocytes. This raises the question why in vivo in the chronically injured or cirrhotic liver, apoptosis is not the prevailing mode of hepatocyte cell death. It appears that the hepatocyte in the chronically injured liver is somehow resistant against apoptotic cell death. Several mechanisms have been proposed which contribute to this resistant phenotype [4,6–9]. First of all, the expression of the bile acid importer NTCP (Naþ-dependent taurocholate cotransporting polypeptide) is downregulated in chronic liver diseases, in particular cholestatic liver diseases [6]. Since bile acid-induced apoptosis is absolutely dependent on bile acid uptake [7], reduced NTCP expression contributes to the protection against bile acid induced apoptosis. Furthermore, in cholestasis hepatocytes are exposed to a mixture of many different bile acids, including pro-, antiand non-apoptotic bile acids. The actual apoptotic potential of this bile acid mixture remains to be determined. Recently, another mechanism of increased resistance against apoptosis in the cholestatic liver has been described: activation of the transcription factor NF-kB [4,9]. NF-kB regulates the transcription of numerous inflammation-associated genes, including many anti-apoptotic genes [10]. Indeed, inhibition of NF-kB increases hepatocyte apoptosis in chronic cholestasis [9]. Activation of NF-kB prior to exposure to bile acids protects against bile acid-induced apoptosis, although bile acids themselves do not activate NF-kB [4,7]. In vivo, NF-kB in hepatocytes is activated by cytokines derived from inflammatory cells including Kupffer cells and increased expression of the NF-kB-activating cytokines TNFa and interleukin-1 has been reported in chronic cholestasis [4,11]. Bile acids activate additional survival pathways, such as PI-3/Akt-kinase and the p38 and ERK MAP kinases, in various liver cell types, including hepatocytes, cholangiocytes and stellate cells [7,12–15]. Bile acid-mediated activation of the EGF-receptor and subsequent activation of ERK appears to be a common mechanism in these cell types [12–14]. In this issue of the Journal, Black and colleagues deepen

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عنوان ژورنال:
  • Journal of hepatology

دوره 40 6  شماره 

صفحات  -

تاریخ انتشار 2004