**7. Proposed conceptual diagram of apoptosis process in hepatocytes**

Apoptosis is an indispensable process in line with cell proliferation for maintenance of tissue homeostasis and health by removal of injured and/or aged cells. This is especially important in the liver where cells are exposed to toxins and viruses [1]. Any loss of balance between cell death and proliferation due to excessive or insufficient apoptosis always leads to pathologic conditions due to unstable state. In the liver, massive hepatocyte apoptosis is observed in acute hepatic failure, and persistent hepatocyte apoptosis is associated with fibrilization, chronic dysfunction and cancerous transformation of the liver [86]. Apoptosis is induced by various intracellular and extracellular stimuli. In all types of hepatocytes, death receptors (especially Fas) are universally expressed [87], and hepatocyte apoptosis is usually transmitted by external pathways. Especially, activations of Fas and TNF-R1 are correlated with hepatocyte apoptosis in various liver diseases including viral hepatitis, fulminant hepatitis, cholestatic liver disease, alcoholic hepatitis, non-alcoholic fatty-liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), Wilson's disease, and ischemiareperfusion injury [88]. In the study of cholestasis, because no liver injury was observed after ligation of the common bile duct (a model of extrahepatic cholestasis) in Fas-knockout mice, high levels of toxic intracellular bile salts were speculated to increase Fas in the cell membrane resulting in the activation of the receptor [89, 10]. Furthermore, apoptosis is induced via ER stress. Caspase-8 activated via death receptor may regulate ER stress mediated by BAP31 on ER [54]. In alcoholic liver injury, ROS generation is enhanced via NOX, and the excessive ROS interact with Fas death receptor [8] to induce mitochondriamediated and ER stress-mediated apoptosis. Taken together, we propose a diagram showing the mechanism of hepatocyte apoptosis as seen in Fig. 8.

Some Findings on Apoptosis in Hepatocytes 219

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**Figure 8.** Schematic diagram of apoptotic pathway.
