Hepatocyte Death: A Clear and Present Danger

Abstract

The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-xL and Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded protein response contributes to hepatocyte cell death during alterations of lipid and fatty acid metabolism. Finally, the current information implicating RIP kinases in necrosis provides an approach to more fully address this mode of cell death in hepatocyte injury. All of these processes contributing to hepatocyte injury are discussed in the context of potential therapeutic strategies.

The effect of sea anemone (H. magnifica) venom on two human breast cancer lines: death by apoptosis

“…The values are shown as mean ± SEM, n = 3. *Significantly different from the untreated control (0 lg/ml) at p \ 0.05 Malhi et al 2010). Our findings presented here, believed to be the first of their kind for breast cancer cells, demonstrate that H. magnifica venom extract induces apoptosis through the activation of caspases.…”

Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6

“…Infection of liver-specific adenoviruses may cause inflammatory responses and initial apoptosis in the infected sites to subsequently recruit innate inflammatory cells including Kupffer cells. As previously reported about hepatocyte cell death 57 , infiltrated Kupffer cells may promote the activation of hepatic stellate cells which further develop into myofibroblasts. The activated myofibroblasts may secrete TGF-b1, which eventually amplify liver apoptosis in the A20 knockdown animal model.…”

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

“…Bile acids play an important role in the enterohepatic system, but the corresponding cytotoxicity to hepatocytes should also be addressed [1,2] . Numerous studies have suggested that the intrahepatic accumulation of bile acids may directly or indirectly cause further damage to the liver [3] . One of the hypotheses regarding the pathophysiology of cholestasis is that accumulated hepatic bile acids directly induce cell apoptosis, as supported by studies on rat hepatocytes and human hepatoma lines [4,5] .…”