RIPK1 suppresses a TRAF2-dependent pathway to liver cancer

Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis

“…These results appear to be in contrast with the finding that knockdown or knockout of Ripk1 did not compromise TNF-induced NF-κB activation in hepatocytes (20,22,24). This discrepancy is most likely due to differences in the quantitative assessment of NF-κB signaling, as extensively discussed in previous studies on the role of RIPK1 in death of RIPK1-deficient hepatocytes is consistent with the model of 2 different pathways inducing apoptosis downstream of TNFR1, one that is RIPK1 dependent and one that is TRADD dependent (39).…”

“…We found that RIPK1 prevents endotoxin-induced liver damage by inhibiting TNFR1-induced hepatocyte death. These results are in agreement with recent reports showing that RIPK1-deficient hepatocytes were sensitive to TNF-induced death and that mice with LPC-specific Ripk1 knockout were highly susceptible to ConA-or LPS-induced liver damage (20)(21)(22)24). Our genetic studies showed that TNF induces hepatocyte death in RIPK1-deficient hepatocytes by activating TNFR1-TRADD-FADD-dependent apoptosis both in vivo and in vitro ( Figure 8A).…”

“…Primary hepatocytes from RIPK1 LPC-KO FADD LPC-KO mice had viability similar to that of control Ripk1 fl/fl hepatocytes, showing that RIPK1-deficient hepatocytes die by FADD/caspase-8-mediated apoptosis (Supplemental Figure 1D). Deficiency in TNFR1 could only partially reduce the spontaneous death of RIPK1-deficient primary hepatocytes, consistent with the partial protective effect of or TRAF2 (Traf2 fl/fl Alfp-Cre mice) did not cause spontaneous liver injury, mice with combined ablation of RIPK1 and TRAF2 in LPCs developed severe chronic cholestatic liver disease that resulted in the development of liver tumors by the age of 1 year (20). LPCspecific knockout of caspase-8 fully prevented liver damage and tumorigenesis in these mice, showing that combined loss of RIPK1 and TRAF2 sensitizes hepatocytes to caspase-8-dependent apoptosis that drives chronic liver disease and tumorigenesis (20).…”

“…Moreover, administration of LPS caused severe liver injury in RIPK1 LPC-KO mice by inducing TNF-dependent hepatocyte apoptosis (20,21). Interestingly, although LPC-specific deficiency of either RIPK1…”

“…Mice lacking RIPK1 specifically in LPCs (Ripk1 fl/fl Alfp-Cre mice, hereafter referred to as RIPK1 LPC-KO mice) did not develop spontaneous liver disease, showing that RIPK1 is not required for normal liver homeostasis under steady-state conditions (16,(20)(21)(22)(23)(24). However, RIPK1…”