Death receptor activation-induced hepatocyte apoptosis and liver injury.
The TNFalpha receptor super-family consists of several members sharing a sequence homology in a unique function domain, the death domain, which is located in the intracellular portion of the receptor. These so-called death receptors, including Fas, TNF-R1 and TRAIL-R1/TRAIL-R2, are expressed on hepatocytes. When stimulated by their ligands, FasL, TNFalpha or TRAIL, respectively, the death receptors can activate multiple death domain-initiated apoptosis programs, including both extrinsic and intrinsic pathways. A cascade of caspases is activated, which cleave proteins important for the cell structure and function. Activation of the intrinsic pathway also leads to mitochondrial release of several apoptotic proteins and mitochondrial dysfunction, which kill the cell through both caspase-dependent and caspase-independent mechanisms. Death receptor-induced hepatocyte apoptosis contributes to the development of a number of liver diseases, including viral hepatitis, inflammatory hepatitis, Wilson's disease, alcoholic liver disease, endotoxiemia-induced liver failure and ischemia/reperfusion-induced liver damage. This article comprehensively reviews the mechanisms of induction and regulation of death receptor-initiated apoptosis in hepatocytes, examines how these molecular events affect our understanding of the pathogenesis of these diseases and further discusses the potential therapeutic application of the knowledge. We hope we can provide a cohesive and integrated perspective on the many aspects of these complicated processes.
Yin
Xiao-Ming
XM
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. xmyin@pitt.edu
Ding
Wen-Xing
WX
D000818:Animals; D017209:Apoptosis; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D008099:Liver / Q000293:injuries* / Q000503:physiopathology; D008107:Liver Diseases / Q000145:classification / Q000473:pathology / Q000503:physiopathology; D008930:Mitochondria, Liver / Q000473:pathology / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*
D018124:Receptors, Tumor Necrosis Factor