Fig. 7. Proposed model for the role of interleukin-1β signaling in leptin-induced hepatocyte death. Leptin induces maturation of interleukin-1β (IL-1β) through NLRP3 inflammasomes signaling, which itself was found to be activated via ER stress-dependent mechanism in our previous report (
Baral and Park, 2021). Once IL-1β is activated, it is secreted into the extracellular milleu, where it binds to the type-I interleukin-1 receptor (IL-1R1) and transmits the signal that induce apoptosis and cell cycle arrest in hepatocytes. Mechanistically, conformational change of IL-1R1 upon binding with IL-1β leads to inactivation of AKT, which plays a role in the survival and proliferation of hepatocyte. Inactivation of AKT causes dephosphorylation (at Ser 9) and subsequent activation of GSK3β, further resulting in activation of the stress kinase p38MAPK. Finally, p38MAPK signaling critically contributes to p16-dependent cell cycle arrest and apoptotic cell death. Illustration created with BioRender.com.
