Cellular Injury in Liver Diseases by Wen-Xing Ding & Xiao-Ming Yin

Author:Wen-Xing Ding & Xiao-Ming Yin
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

6.4 Mechanisms of Alcohol-Induced Apoptosis in Hepatocytes

In general, apoptosis can either be triggered through intrinsic (mitochondria) or extrinsic (death receptor) pathway. Both intrinsic and extrinsic apoptotic pathways appear to play a role in alcohol-induced cell death in hepatocytes.

6.5 Activation of Mitochondrial (Intrinsic) Apoptotic Pathway by Alcohol

Various apoptotic stimuli, including DNA damage, oxidative stress, or deprivation of hormone or growth factor, can activate the mitochondrial apoptotic pathway or the intrinsic pathway (Yin and Ding 2003). Following the activation of the intrinsic apoptotic pathway, a number of apoptotic factors, such as cytochrome c, second mitochondria-derived activator of caspase (Smac/DIABLO), HtrA2/Omi, apoptosis inducing factor (AIF ), and endonuclease G, are released from mitochondria. Cytosolic cytochrome c then binds to Apaf-1 and caspase-9 to form a heptameric complex known as “Apoptosome,” which subsequently activates caspase-9 in the presence of dATP (Li et al. 1997). Activated caspase-9 further cleaves and activates downstream executioner caspases, such as caspase-3, -6, and -7. Cells with the deficiency of Apaf1, caspase-9, or caspase-3 are resistant to apoptosis following intrinsic apoptotic stimuli, highlighting the importance of this pathway. Concomitantly, Smac/DIABLO is also released into the cytosol, where it binds to the inhibitor of apoptosis proteins (IAPs), such as XIAP, to abolish their inhibitory effects on caspases. More than 400 caspase substrates have been identified that are cleaved by activated executioner caspases resulting in the characteristic morphological features of apoptosis such as DNA fragmentation/condensation, externalization of phosphatidylserine, and formation of apoptotic bodies.

The Bcl-2 family proteins are a group of evolutionarily conserved proteins that regulate apoptosis mainly on mitochondria. Bcl-2 family proteins consist of antiapoptotic and proapoptotic members, and all members possess conserved α-helices with sequence conservation clustered in BCL-2 homology (BH) domains . Antiapoptotic proteins such as Bcl-2 and Mcl-2 have all segments of BH1–BH4 domain, whereas proapoptotic proteins lack the first α-helical BH4 domain and are further subdivided into “multidomain” and “BH3-only” molecules. The multidomain proapoptotic Bcl-2 family proteins Bax and Bak form a requisite gateway on regulating the intrinsic mitochondrial apoptotic pathway. Bax is a cytosolic protein whereas Bak resides at the mitochondria membrane. Upon an intrinsic death signal, Bax translocates from cytosol to mitochondria and inserts into the outer mitochondrial membrane by forming homo-oligomers. Bak also undergoes a conformation change and oligomerization resulting in the permeabilization of the outer mitochondrial membrane followed by releasing of apoptotic proteins from the inter-membrane space (Wei et al. 2001). The propapoptotic BH3-only members such as Noxa and Puma only have amphipathic α-helical BH3 region. The BH3-only proteins are regulated at the transcriptional regulation or posttranslational modification and reside upstream in the pathway in response to death signals. The BH3-only proteins still require downstream Bax and Bak to trigger apoptosis, whereas antiapoptotic proteins such as Bcl-xL and Mcl-1 inhibit apoptosis by binding and sequestering “BH3-only” proteins to prevent the activation of Bax and Bak (Scorrano and Korsmeyer 2003).

Chronic ethanol feeding has been shown to increase the expression of Bcl-xL and Bax in the mouse livers. In cultured AML12 cells (immortalized mouse hepatocytes), it

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