The strength of the Fas ligand signal determines whether hepatocytes act as type-1 or type-2 cells in murine livers

Apoptosis induced by Fas activation has been implicated in a variety of liver diseases.^1,2 Binding of the FasL to its receptor triggers intracellular activation of caspase-8.^3–6 In type I cells caspase-8 activates the effector caspases which suffices to kill the cell. In type II cells caspase-8 requires a mitochondria-amplification loop to induce cell death.^7,8 Bid was identified to mediate the apoptotic signal from the cell surface to the mitochondria.⁹ Bid has been shown to be critical for Fas-induced apoptosis in hepatocytes, which are therefore regarded as type II cells. Furthermore, some studies have suggested that phosphorylation of Bid may determine the apoptotic function of Bid and may act as a switch to non-apoptotic functions.^{10, 11} The aim of this study was to evaluate the role of Bid for FasL-induced apoptosis in murine livers. Jo2 and a hexameric form of sFasL (MegaFasL) were used to induce apoptosis in WT, Bid-/-, Bid transgenic mice expressing a non-phosphorable form of Bid and lpr mice. Apoptosis sensitivity was determined in healthy mice and in mice following bile duct ligation or partial hepatectomy. Whereas loss of Bid protects mice against Jo2-induced liver failure, Bid-/- mice were highly sensitive to MegaFasL-induced apoptosis. Remarkably, MegaFasL treated Bid-/- mice showed a typical type I signaling behavior without activation of the mitochondrial amplification loop. In contrast to previous in vitro findings, phosphorylation of Bid does not affect the sensitivity of hepatocytes to FasL-mediated apoptosis in vivo. Our data suggest that Bid is not absolutely required for FasL-induced apoptosis and mainly amplifies a weak death receptor signal in quiescent and nonquiescent hepatocytes rendering the liver more sensitive to FasL-induced apoptosis. Thus, depending on the efficacy of Fas receptor activation, hepatocytes and nonparenchymal cells can either behave as type I or type II cells.

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