Figure 1.

Proposed mechanisms of T/UDCA inhibition of apoptosis. T/UDCA negatively modulates the mitochondrial pathway by inhibiting Bax translocation, ROS formation, cytochrome c release, and caspase-3 activation. T/UDCA protects against mitochondrial membrane permeabilization and decreased ΔΨm, which reduces ROS production and apoptosis. T/UDCA can also interfere with the death receptor pathway, inhibiting caspase-3 activation. Moreover, T/UDCA inhibits apoptosis associated with ER stress by modulating intracellular calcium levels and inhibiting calpain and caspase-12 activation. Importantly, T/UDCA interacts with NSR, leading to NSR/hsp90 dissociation and nuclear translocation of the T/UDCA/NSR complex. Once in the nucleus, T/UDCA reduces apoptosis by modulating the E2F-1/p53/Bax pathway, inhibiting MDM2/p53 association, decreasing BAX, PUMA and NOXA expression, reducing p53 transactivation and DNA binding activity, and increasing p53 degradation. Finally, T/UDCA downregulates cyclin D1 and Apaf-1, further inhibiting the mitochondrial apoptotic cascade.

Abbreviations: Cyt c, cytochrome c; Hsp90, heat shock protein 90; T/UDCA, tauroursodeoxycholic/ursodeoxycholic acid.

Reprinted with permission from Amaral et al, 2009.²