Figure 5.

The central role of hepatocyte apoptosis in liver injury. Vulnerable hepatocytes undergo apoptosis when stressed. Apoptosis can be initiated via Kupffer cell release of TNF-α, leading to activation of JNK. Activated NK and NK T cells release Fas or TRAIL, and interferon gamma, which up-regulates Fas or TRAIL release, leading to death receptor–mediated hepatocyte apoptosis. Hepatocyte apoptosis can also occur via activation of the intrinsic pathway (not shown here). Apoptotic hepatocytes are engulfed Kupffer cells, leading in turn to their activation. Activated Kupffer cells secrete TNF-α, interleukins, and interferon to promote the inflammatory response. They also secrete transforming growth factor β, leading to activation of stellate cells. Stellate cells can also be directly activated by apoptotic bodies. Activated stellate cells secrete collagen type I, leading to liver fibrosis. Attenuation of hepatocyte apoptosis, or forced apoptosis of activated stellate cells, such as with proteasomal inhibitors or TRAIL, can lead to resolution of fibrosis.