Death receptor-mediated apoptosis and the liver.

Abstract

1. IntroductionLiver injury and fibrosis are both cardinal features ofchronic human liver diseases. The composite mechanismsculminating in these processes are complex and intertwined.Apoptosis, a stereotyped morphologic form of cell death,however, likely plays a critical role both in liver injury andits sequela, fibrosis. More importantly, therapeutic modula-tion of apoptosis has the potential to alter the course ofhuman liver disease. Therefore, it is both timely and topicalto provide an overview on apoptosis focusing on the liver.Unlike other reviews [1–3], this overview will not attempt toprovide a comprehensive and encylcopedical repository ofinformation on liver cell apoptosis. Rather, the interplay ofapoptosis in human liver diseases will be emphasized, andcurrent-working models of apoptosis in liver injury will bedelineated. At times, this article will hopefully be visionaryand provocative highlighting areas ripe for future investiga-tion and clinical studies/trials.Apoptosis may occur by two fundamental pathways: (i)the death receptor (DR) or extrinsic pathway; and (ii) themitochondrial or intrinsic pathway. The DR pathwayinvolves ligation and/or oligomerization of cell surfacereceptors to trigger the apoptotic pathway. Liver cells richlyexpress DRs, perhaps because of evolutionary pressure toeradicate hepatotropic viruses. Indeed, immunocytes useDR-mediated apoptosis, in part, to eradicate virally infectedcells. In contrast, the mitochondrial pathway is triggered bya variety of intracellular stress responses (DNA damage,changes of intracellular Ca