Abstract
The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.
Highlights
The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver
We could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptorinteracting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis
To explore the hepatic function of the JNK pathway during aging, Jnk1FL mice and Jnk2FL mice were interbred with alfp-cre mice to generate animals with conditional deletion of Jnk1 (JNK1LPC-KO), Jnk2 (JNK2LPC-KO), or both Jnk1 and Jnk2 (JNK1/2LPC-KO) in liver parenchymal cells (LPCs) including hepatocytes and cholangiocytes, as JNK1/2−/− mice are embryonically lethal (SI Appendix, Fig. S1 A and B) [6,7,8,9]
Summary
The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. We showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease These data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. They provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging. It had not been recognized that JNK plays a fundamental role in maintaining liver homeostasis and preventing the formation of biliary cysts in aging mice These observations call for caution in all long-term pharmacological inhibition strategies targeting the JNK pathway. The specific overexpression of RIPK1 in cysts of a subset of patients with polycystic liver disease suggests that RIPK1 might be mechanistically involved in the pathogenesis of human biliary cysts
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