Leptin induces apoptotic and pyroptotic cell death via nlrp3 inflammasome activation in rat hepatocytes

Abstract

Leptin, a hormone that is predominantly produced by adipose tissue, is closely associated with various liver diseases. However, there is a lack of understanding as to whether leptin directly induces cytotoxic effects in hepatocytes as well as the mechanisms that are involved. Inflam-masomes, which are critical components in the innate immune system, have been recently shown to modulate cell death. In this study, we examined the effect of leptin on the viability of rat hepato-cytes and the underlying mechanisms, with a particular focus on the role of inflammasomes activa-tion. Leptin treatment induced cytotoxicity in rat hepatocytes, as determined by decreased cell via-bility, increased caspase‐3 activity, and the enhanced release of lactate dehydrogenase. NLRP3 in-flammasomes were activated by leptin both in vitro and in vivo, as determined by the maturation of interleukin‐1β and caspase‐1, and the increased expression of inflammasome components, including NLRP3 and ASC. Mechanistically, leptin‐induced inflammasome activation is mediated via the axis of ROS production, ER stress, and autophagy. Notably, the inhibition of inflammasomes by treatment with the NLRP3 inhibitor or the IL‐1 receptor antagonist protected the hepatocytes from leptin‐induced cell death. Together, these results indicate that leptin exerts cytotoxic effects in hepatocytes, at least in part, via the activation of NLRP3 inflammasomes.