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The liver's dance with death: Two Bcl‐2 guardian proteins from the abyss

The liver is an organ of immense complexity which carefully guards its secrets and continues to reveal and conceal its intricacies. This large organ regulates intermediary metabolism, detoxifies endobiotics and xenobiotics, manufactures critical circulating proteins, has a pivotal excretory function (i.e., bile formation), and can be viewed as a key participant of the innate immune system. In vertebrates, the liver is essential for survival because no other organ can compensate for this multiplicity of functions. A key liver cell participating in each of these processes is the hepatocyte. Disturbances in any of the aforementioned intrinsic hepatic functions and/or exuberant activation of the innate immune system stresses the organ, endangering hepatocyte survival. Indeed, biomarkers for hepatocyte injury—serum aminotransferases—are present in all humans. What constitutes elevation of these biomarkers separating an injured from a “healthy” liver is uncertain and is subject of intense medical interest.1 We posit here that the mere presence of aminotransferases in the circulation implies basal hepatocyte stress and turnover, and perhaps some level of stress and hepatocyte death is simply to be expected given the burden of the aforementioned hepatocyte functions. 
 
Over the last several decades, science has provided considerable insight into how cells sense and succumb to stress. We now realize that cell death commonly occurs by apoptosis, a process characterized by activation of intracellular proteases termed caspases.2 Once these zymogens are activated, they demolish the cell resulting in nuclear fragmentation, cell shrinkage, and scission of the cell into membrane-defined remnants, termed apoptotic bodies. Indeed, human cell apoptosis has long been recognized in liver biopsies,3,4 and apoptotic bodies were initially referred to by hepatopathologists as Councilman bodies. 
 
Apoptosis occurs by an extrinsic death receptor pathway or by an intrinsic intracellular pathway culminating in mitochondrial dysfunction. In the hepatocyte, these pathways converge in that the death receptor pathway also requires mitochondrial dysfunction for efficient apoptosis.5 The mitochondrial pathway of cell death is controlled by interactions between members of the Bcl-2 family of proteins.6 These proteins can be categorized into subsets. The guardians or antiapoptotic members of this family include Bcl-2, Bfl-1/A1, Mcl-1, Bcl-xL and Bcl-w. The multidomain executioners or proapoptotic members of this family include Bcl-2-associated X protein (Bax) and Bak.6 Bax and Bak are essential for cell death, directly induce mitochondrial dysfunction and are often redundant in that expression of one compensates for the lack of the other. Although the multidomain proteins share four Bcl-2 homology domains, the messengers or biosensors of cell death display only the third Bcl-2 homology domain. These proteins, referred to as BH3-only proteins, include BH3-interacting domain death agonist (Bid), Bim, Bmf, p53 up-regulated modulator of apoptosis (Puma), Noxa, Hrk, Bad, and Bik. The mechanisms by which these messengers induce cell death remain controversial; however, Bid, Bim, and Puma are thought to directly activate the executioners Bax and/or Bak,7-9 whereas the others may antagonize the ability of the antiapoptotic proteins to prevent Bax and Bak activation.10 Thus, the antiapoptotic proteins of this family are essential to prevent apoptosis upon activation of BH3-only proteins following a death stimulus.