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. Author manuscript; available in PMC: 2010 Nov 1.
Published in final edited form as: Clin Liver Dis. 2009 Nov;13(4):565–580. doi: 10.1016/j.cld.2009.07.003

Figure 1. Hepatocyte Apoptosis during liver injury leads to Inflammation and Fibrosis.

Figure 1

During liver injury, ligation of surface death receptors by FasL, TNFα or TRAIL (extrinsic apoptosis pathway), promotes hepatocyte apoptosis, through recruitment of cytoplasmic adaptor molecules and activation of caspase-8. Caspases amplify the apoptotic signaling cascade, and commits the hepatocyte to the final execution (apoptosis) pathway (activated caspase-3). The organelle-based (intrinsic apoptosis pathway), non-receptor mediated apoptosis-pathway involves various stimuli (growth factors, cytokines, free radicals, hypoxia, viral infections and toxins) that disrupt the mitochondrial permeability transition pore, and loss of the mitochondrial transmembrane potential. These changes lead to the release of pro-apoptotic proteins, which initiate the mitochondrial-apoptosis pathway. Clearance of apoptotic bodies occurs through phagocytosis by resident macrophages (Kupffer cells) and hepatic stellate cells. Engulfment of apoptotic bodies is associated with increased ROS production and activation of transcription factors, NF-κB. In turn, this leads to enhanced production of pro-inflammatory cytokines (TNFα) and chemokines (MIP2, IL8). TNFα may further drive the extrinsic apoptosis pathway through a feed-forward, paracrine loop. Phagocytosis of apoptotic bodies also induces the production of the pro-fibrogenic cytokines, TGFβ and IL13, via the PI3K and MAPK pathways.