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Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis
Trieu-My Van, … , Nikoletta Papadopoulou, Manolis Pasparakis
Trieu-My Van, … , Nikoletta Papadopoulou, Manolis Pasparakis
Published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2662-2677. https://doi.org/10.1172/JCI92508.
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Research Article Hepatology Inflammation

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

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Abstract

The mechanisms that regulate cell death and inflammation play an important role in liver disease and cancer. Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF receptor 1 (TNFR1) signaling. In contrast, mice with LPC-specific knockout of Ripk1 showed reduced diethylnitrosamine-induced (DEN-induced) liver tumorigenesis that correlated with increased DEN-induced hepatocyte apoptosis. Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, showing that kinase-independent functions of RIPK1 promote DEN-induced hepatocarcinogenesis. Moreover, mice lacking both RIPK1 and TNFR1 in LPCs displayed normal tumor formation in response to DEN, demonstrating that RIPK1 deficiency decreases DEN-induced liver tumor formation in a TNFR1-dependent manner. Therefore, these findings indicate that RIPK1 cooperates with NF-κB signaling to prevent TNFR1-independent hepatocyte apoptosis and the development of chronic liver disease and cancer, but acts downstream of TNFR1 signaling to promote DEN-induced liver tumorigenesis.

Authors

Trieu-My Van, Apostolos Polykratis, Beate Katharina Straub, Vangelis Kondylis, Nikoletta Papadopoulou, Manolis Pasparakis

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Figure 1

RIPK1 prevents LPS-induced liver injury by inhibiting TNF-mediated hepatocyte death.

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RIPK1 prevents LPS-induced liver injury by inhibiting TNF-mediated hepat...
(A and B) Graphs depicting survival (A) and serum ALT levels (B) of 9-week-old Ripk1fl/fl and RIPK1LPC-KO mice at 5.5 hours after LPS injection. ***P < 0.005, Mantel-Cox test (A); ***P < 0.005, 1-way ANOVA (B). (C) Representative images of liver sections from the indicated mice immunostained for CC3 (n = 4–5 per genotype). Scale bar: 100 μm. (D) Immunoblot analysis for CC3 and cleaved PARP1 in liver lysates from the indicated mice. Actin was used as loading control. (E) Graph depicting serum TNF levels of 9-week-old Ripk1fl/fl (0 hours, n = 4; 1 hour, 2 hours, 8 hours, n = 6) and RIPK1LPC-KO mice (0 hours, 1 hour, 2 hours, n = 6; 8 hours, n = 2) injected with LPS (mean ± SEM). (F) Graph depicting survival of primary hepatocytes from Ripk1fl/fl or RIPK1LPC-KO mice cultured for 24 hours in the presence or absence of anti-TNF, anti-FasL, or Z-VAD-FMK. ***P < 0.005; **P < 0.01, 1-way ANOVA. (G) Immunoblot analysis of p-IκBα and IκBα in total protein lysates of Z-VAD-FMK–treated Ripk1fl/fl and RIPK1LPC-KO primary hepatocytes stimulated with TNF for the depicted time periods. (H) Immunoblot analysis for RelA in cytoplasmic and nuclear extracts from Z-VAD-FMK–stimulated Ripk1fl/fl or RIPK1-deficient hepatocytes. Actin and lamin A/C were used as loading controls. (I) qRT-PCR analysis of NF-κB target gene expression in TNF-stimulated Ripk1fl/fl and RIPK1LPC-KO primary hepatocytes in the presence of Z-VAD-FMK. Mean ± SEM. ***P < 0.005, 2-way ANOVA. Graphs show relative mRNA expression normalized to Tbp. (J and K) Graphs depicting survival (J) and serum ALT levels (K) of 9-week-old mice with indicated genotypes 5.5 hours after LPS injection. Serum ALT levels of Ripk1fl/fl and RIPK1LPC-KO mice are included in Figure 1B. ***P < 0.005, Mantel-Cox test (J); *P < 0.05, 1-way ANOVA (K).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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