PMC

 Evidence of hepatocyte apoptosis in vivo. Histopathological examination of a liver section from a patient with hepatitis C virus by conventional haematoxylin-eosin staining shows an apoptotic body (also known as Councilman body, black arrow) surrounded by immune cells, such as T lymphocytes (white arrows) and macrophages.

 The link between apoptosis and fibrosis in the liver. Schematic representation of the molecular mechanisms involved in the proposed model linking hepatocyte apoptosis and liver fibrosis. Different injuries on the liver result in hepatocyte apoptosis. The generated apoptotic bodies are cleared by phagocytosis by Kupffer cells and hepatic stellate cells, which enhances their expression of profibrogenic genes and death ligands, such as Fas ligand. Persistent activation of these cells promotes further hepatocyte apoptosis, progression of fibrosis, hepatic inflammation, and liver damage.

 Therapeutic modulation of apoptosis in liver diseases. Imbalance between cell proliferation and cell death in the liver contributes to the pathogenesis of several liver diseases. Excessive apoptosis is associated with acute diseases, such as acute and fulminant hepatitis, as well as with chronic diseases, such as chronic hepatitis, alcoholic liver disease, cholestatic liver disease, and non-alcoholic steatohepatitis (NASH). Sustained apoptosis also causes persistent inflammation and promotes fibrogenesis. In contrast, deficient apoptosis contributes to the development of liver and biliary cancer. Therapeutic strategies currently in use or potentially useful to modulate apoptosis in liver diseases are depicted. TRAIL, tumour necrosis factor related apoptosis inducing ligand (TRAIL); HSC, hepatic stellate cells; siRNA, small interfering RNA.

 Death receptor mediated (extrinsic) pathway of apoptosis. Schematic representation of signalling through the main death receptors (Fas/CD95, tumour necrosis factor receptor 1 (TNF-R1), tumour necrosis factor related apoptosis inducing ligand receptors 1 and 2 (TRAIL-R1 and TRAIL-R2)). Engagement of death receptors by their cognate ligands results in oligomerisation of the receptor and recruitment of adaptor proteins (Fas associated protein with death domain (FADD), TNF-R1 associated death domain protein (TRADD)), which in turn bind the inactive initiator caspase-8 and/or -10. The resulting complex is referred to as the death inducing signalling complex (DISC). The close proximity of several procaspase molecules results in activation of the caspase by self processing. Active initiator caspases can directly activate downstream caspases such as caspase-3, -6, and -7, or engage the mitochondrial pathway of apoptosis by cleavage and activation of the BH3 only protein Bid (see fig 3 for details).

 Mitochondria mediated (intrinsic) pathway of apoptosis. Various stimuli, including ultraviolet (UV) and γ-irradiation, endoplasmic reticulum (ER) stress, growth factor deprivation, and oxidative stress with production of reactive oxygen species (ROS) trigger the intrinsic pathway via activation of proapoptotic members of the Bcl-2 family of protein (that is, Bax, Bak), which oligomerise on the outer mitochondrial membrane and cause mitochondrial dysfunction. The proapoptotic action of Bax and Bak can be antagonised by the antiapoptotic members of the same family Bcl-2 or Bcl-X_L. Following mitochondrial dysfunction, several apoptogenic factors, including cytochrome c and second mitochondria derived activator of caspases/direct IAP binding protein with low pI (SMAC/DIABLO), are released from the mitochondrial intermembrane space into the cytosol. Cytochrome c binds to the adaptor apoptosis associated factor 1 (Apaf-1) and recruits procaspase-9 to form a complex named apoptosome which, in an APT requiring reaction, results in activation of the initiator caspase-9. Caspase-9, in turn, activates the effector caspases (caspase-3, -6, and -7) responsible for degradation of cellular substrates. SMAC/DIABLO contributes to caspase activation by binding and inactivating the endogenous inhibitor of caspases IAPs.