Bid, a critical mediator for apoptosis induced by the activation of Fas/TNF-R1 death receptors in hepatocytes

The Bcl-2 family proteins consist of both anti-apoptosis and pro-apoptosis members chat regulate apoptosis typically at the mitochondrial level, mainl y by controlling the release of cytochrome c and other mitochondrial apopto tic events. However, death signals mediated by Fas/TNF-R1 receptors can usu ally activate caspases directly, bypassing the need for mitochondria and es caping the regulation by Bcl-2 family proteins. Bid is a novel pro-apoptosi s Bcl-2 family protein that is activated by Caspase 8 in response to Fas/TN F-R1 death receptor activation. Activated Bid is translocated to mitochondr ia and induces cytochrome c release, which in turn activates the downstream caspases. This Bid-mediated pathway is critical in hepatocyte apoptosis in duced by Fas/TNF-R1 engagement, where direct activation of cytosolic caspas e cascade seems inefficient. The dependence on Bid, and thus on the mitocho ndrial cytochrome c release, of hepatocyte apoptosis induced by the death r eceptors also renders it sensitive to the inhibitory regulation by the anti -apoptosis members of the Bcl-2 family proteins, such as Bcl-2 and Bcl-xL. Moreover, the revealing of this death pathway in hepatocytes is important t o the understanding of the pathogenesis of a number of hepatic diseases suc h as hepatitis or endotoxemia-related hepatic failure.