Apoptosis in liver disease.

The description of the morphological hallmarks of programmed cell death, apoptosis, in 1972 by Kerr, Wyllie and Currie started a field of research that revolutionized our understanding of cellular proliferation, tissue homeostasis and pathophysiology of many diseases. In the following years, a series of proteins involved in signaling and intracellular death pathways were identified and 30 years later the Noble Prize for physiology and medicine was awarded to S. Brenner, H. R. Horvitz and J. E. Sulston for their discoveries related to describing the mechanisms of cell death (apoptosis). The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding in many liver diseases. The most detailed analyzed mode of apoptosis involves a cell surface-based receptor-ligand system. Death receptors are typically members of the tumor necrosis factor-receptor superfamily and comprise an intracellular death domain. Following ligand binding to the receptor, intracellular adapter molecules are recruited to the receptor and subsequently transmit the apoptotic signal. Intracellular organelle-dependent signaling occurs, and effector molecules then augment the receptor-initiated apoptosis process. Cell death and degradation follows the activation of a highly regulated set of cytosolic and nuclear proteases and DNAses. Receptor-independent activation of the apoptotic process can occur as part of the cytotoxicity related to UV radiation, chemotherapeuticals or other DNA-damaging agents through activation of intracellular sensors of cellular integrity, e.g. the tumor suppressor gene p53. In contrast to necrosis, apoptosis is not commonly accompanied by an inflammatory response that causes collateral cell damage. The apoptotic program is highly effective in eliciting cell death and thus must be tightly controlled. This is achieved through continuous integration of pro- and antiapoptotic signals at the individual cell level. Dysregulation of the apoptotic process, resulting in too much or too little cell death, has potentially devastating effects and has been implicated in many forms of liver disease like acute liver failure or hepatocellular carcinoma. This review will focus initially on recent progress in signaling events of hepatocellular apoptosis and subsequently discuss the consequences for the hepatic pathophysiology that involves disarrangement of hepatocellular apoptosis.