Bile acid induced apoptosis 1) Bile acids promote both Fas and TRAIL-R2/DR5 oligomerization by distinct mechanisms. Bile acids enhance TRAIL-R2/DR5 mRNA transcription and protein expression. In contrast, cellular Fas expression level is not altered by bile acids; however, bile acids stimulate Golgi-associated and microtubuledependent Fas trafficking to the plasma membrane by JNK- and PKCdependent processes, resulting in an increased density of cell surface Fas. The increased cell surface density of these death receptors likely promotes death receptor oligomerization, initiating a DISC formation.
2) Toxic bile acids promote death receptor-mediated cell death signaling. Toxic bile acids induce oligomerization of cell surface death receptors. FADD promotes recruitment of procaspase-8/10 to the death-inducing signaling complex (DISC), results in spontaneous activation of caspases via autoproteolytic cleavage, and induce mitochondrial dysfunction including cytochrome c release. Cytosolic cytochrome c then binds to apoptosisactivating factor-1 (Apaf-1), resulting in activation of caspase-9. Caspase-9 can activate effector caspases such as caspases-3, -6, and -7 via a caspase cascade, As a result of excess production, oxidative stress may exaggerate cell death, either enhancing apoptosis or inducing necrosis.
