Death receptors in liver biology and pathobiology
Authors: William A. Faubion, Gregory J. Gores
Journal: Hepatology (1999)

The only thing certain in life is death.Indeed, among the bustle of mitosis and growth, the process of removal of senescent, damaged, or otherwise unwanted cells by apoptosis is simply a matter of business for the organism.Therefore, it is not surprising that nature has not left cell death to chance, but has developed finely tuned mechanisms for cellular disassembly.Analogous to growth regulation by growth factors and receptors, a complementary process exists to regulate cell death using death factors and death receptors.Current information suggests that these death ligands and corresponding receptors are not only important in regulating physiological cell death, but also mediate cell death in human liver diseases.Thus, knowledge regarding how cell death receptors function may help in developing rational therapeutic strategies to ameliorate clinical liver disease.Death receptors are members of the tumor necrosis factor/ nerve growth factor superfamily of receptors.Death receptors include Fas and tumor necrosis factor receptors 1 and 2 (TNF-R1 and TNF-R2), death receptor 3, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors 1, 2, 3, and 4. Apoptosis-inducing death receptors are often characterized by a 60-to 80-amino acid death domain in the cytoplasmic tail of the receptor referred to as the death domain.The death domain functions to recruit adapter molecules important for initiating the death signal (see below).The currently identified death domain containing death receptors, their alternative labels, and the absence or presence of liver expression are summarized in Table 1.Information regarding the absence of liver expression should be interpreted with caution, because the expression of these receptors in the liver is usually based on Northern blot analysis of whole-liver RNA, a technique that may miss expression by a minority liver cell population (e.g., cholangiocytes, stellate cells, etc.).Due to space limitations, we will not discuss the ligands of these receptors.Because death receptor 3 is not expressed in the liver, neither will it be discussed further.[3][4][5] Fas-RECEPTOR Fas-Receptor (APO-1/CD95) has a single membranespanning domain and is expressed in hepatocytes, cholangiocytes (Que F, LaRusso NF, Gores GJ, unpublished observations, March 1997), activated stellate cells, 6 and Kupffer cells. 7An alternatively spliced soluble form of the Fas-Receptor (Fas-R) without the transmembrane-spanning domain can also be expressed by hepatocytes.The soluble form of Fas-R may serve to bind Fas ligand on cytotoxic T cells, thereby minimizing liver injury. 8The importance of the Fas-R in liver pathophysiology and homeostasis has been amply documented by several observations.Injection of Fas-R agonistic antibodies causes death in the mouse associated with fulminant hepatic failure. 9Indeed, these data were the first to highlight the potential dominant role of the Fas-R system in liver injury.The Fas-null mouse, generated by gene targeting, develops liver hyperplasia, likely as a result of growth in the absence of apoptosis. 10Fas-R has been closely correlated with the activity of viral hepatitis. 11-13Indeed, in hepatitis C, the degree of Fas-R expression has been shown to fall with interferon therapy. 14Of particular importance to liver injury, Fas-R expression can be induced and upregulated by inflammatory cytokines such as interleukin-1. 15his raises the intriguing possibility that inflammation from any cause may promote Fas-R-dependent liver injury.Fas-R expression has recently been found to be significantly reduced in particularly aggressive forms of hepatocellular carcinoma, specifically those cancers most poorly differentiated and exhibiting portal vein or extracapsular invasion. 16oss of Fas-R expression by these tumors likely reflects a survival adaptation to avoid cell death by immune surveillance processes (e.g., attack by cytotoxic T lymphocytes).Chemotherapeutic agents may induce apoptosis in hepatocellular carcinoma cells by up-regulating Fas-R expression via a p53-dependent pathway. 17Thus, the Fas-R system plays a critical role in liver cancer biology and the response of hepatocellular cancer to chemotherapeutic agents.The Fas-R-mediated intracellular apoptotic pathway has recently been partially elucidated (Fig. 1).Ligation of the Fas-R results in receptor oligomerization, leading to recruitment of the adapter protein, FADD (Fas-associated protein with death domain) to the death domain of the Fas-R.The prodomain of caspase 8 (a member of the family caspase proteases that play an integral role in the apoptotic process) contains two death effector domains that bind in a homophillic manner to the death effector domains present on FADD. 18he resulting complex is termed the death-inducing signaling complex, or DISC.Recruitment of procaspase 8 molecules to the death-inducing signaling complex results in activation of this protease. 19Activation of caspase 8 via the Fas-R is a major mechanism initiating physiological and pathophysiological hepatocyte apoptosis. 20The mechanisms by which caspase 8 can induce apoptosis are beyond the scope of this review, and the reader is referred to other general overviews on caspases. 21Although alternative mechanisms of Fas-R signaling have been proposed, the FADD knockout mouse is resistant to Fas-mediated apoptosis, suggesting that the FADD-dependent mechanism is dominant. 22Another important caveat is that the mere expression of Fas-R does not imply that the cell is susceptible to apoptosis by Fas ligation.