RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury
| العنوان: | RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury |
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| المؤلفون: | Kerstin Holzer, Jesus M. Banales, Peter Schirmacher, Manolis Pasparakis, Henning Walczak, Vangelis Kondylis, George Kollias, Stephan Singer, Santosh Krishna-Subramanian, Marietta Armaka |
| المصدر: | Cell death and differentiation |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Carcinogenesis, Necroptosis, necroptosis, Chronic liver disease, Cholangiocyte, Article, Hepatitis, 03 medical and health sciences, Liver disease, Mice, 0302 clinical medicine, medicine, Animals, Humans, Kinase activity, Molecular Biology, business.industry, Liver cell, apoptosis, Cell Biology, hepatocellular carcinoma, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Apoptosis, 030220 oncology & carcinogenesis, Hepatocyte, Receptor-Interacting Protein Serine-Threonine Kinases, Chronic Disease, Cancer research, business, liver disease, cholestasis, Signal Transduction |
| الوصف: | Hepatocyte apoptosis is intrinsically linked to chronic liver disease and hepatocarcinogenesis. Conversely, necroptosis of hepatocytes and other liver cell types and its relevance for liver disease is debated. Using liver parenchymal cell (LPC)-specific TGF-beta-activated kinase 1 (TAK1)-deficient (TAK1LPC-KO) mice, which exhibit spontaneous hepatocellular and biliary damage, hepatitis and early hepatocarcinogenesis, we have investigated the contribution of apoptosis and necroptosis in hepatocyte and cholangiocyte death and their impact on liver disease progression. Here, we provide in vivo evidence showing that TAK1-deficient cholangiocytes undergo spontaneous necroptosis induced primarily by TNFR1 and dependent on RIPK1 kinase activity, RIPK3 and NEMO. In contrast, TAK1-deficient hepatocytes die by FADD-dependent apoptosis, which is not significantly inhibited by LPC-specific RIPK1 deficiency, inhibition of RIPK1 kinase activity, RIPK3 deficiency or combined LPC-specific deletion of TNFR1, TRAILR and Fas. Accordingly, normal mouse cholangiocytes can undergo necroptosis, while primary hepatocytes are resistant to it and die exclusively by apoptosis upon treatment with cell death-inducing stimuli in vitro, likely due to the differential expression of RIPK3. Interestingly, the genetic modifications that conferred protection from biliary damage also prevented the spontaneous early lethality that was often observed in TAK1LPC-KO mice. In the presence of chronic hepatocyte apoptosis, preventing biliary damage delayed but did not avert hepatocarcinogenesis. On the contrary, inhibition of hepatocyte apoptosis fully prevented liver tumorigenesis even in mice with extensive biliary damage. Altogether, our results suggest that using RIPK1 kinase activity inhibitors could be therapeutically useful for cholestatic liver disease patients. |
| اللغة: | English |
| تدمد: | 1476-5403 1350-9047 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a89adbee37c60fe425cd9d535ac6e3cf http://europepmc.org/articles/PMC6861136 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a89adbee37c60fe425cd9d535ac6e3cf |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765403 13509047 |
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