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. Inflammasomes, 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 hepatocytes and the underlying mechanisms, with a particular focus on the role of inflammasomes activation. Leptin treatment induced cytotoxicity in rat hepatocytes, as determined by decreased cell viability, increased caspase-3 activity, and the enhanced release of lactate dehydrogenase. NLRP3 inflammasomes 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.

Mechanisms of Inflammasome Activation and Involvement in Liver Disease

“…Maturation of cathepsin B leading to its enhanced secretion from lysosomes encourages direct interaction with NLRP3 inflammasomes and ultimately promotes its activation [42]. In recent years, the axis of autophagy and cathepsin B maturation has emerged as a crucial player in the modulation of inflammasome activation in different conditions [43,44].…”

“…The most well-known among them are the adipokines, namely leptin and visfatin [59,60]. Leptin induces inflammasome activation in diverse cell types, including hepatocytes [43]. Androgens have been reported to stimulate inflammasome activation leading to hepatic fibrosis [61].…”

A Lipid Perspective on Regulated Pyroptosis

“…Leptin can modulate lipid metabolism in hepatocytes, resulting in hepatic steatosis [150]. A study has shown that leptin exerts direct hepatocyte pyroptosis via ROS production/ER stress/autophagy induction/ cathepsin B maturation/NLRP3 inflammasomes axis, leading to potential liver injury [151]. Moreover, leptin can also trigger hepatocyte pyroptosis through CD8 + T lymphocytes.…”

Роль Адипокинов В Формировании Кардиометаболических Нарушений У Человека

“…Среди основных периферических эффектов лептина стоит выделить разобщение окисления и фосфорилирования в жировой ткани, что приводит к липолизу и, как следствие, усилению выработки тепла [15,18]. Описано стимулирующее влияние лептина на процессы апоптоза в жировой ткани за счет высвобождения каспазозависимых белков и образования активных форм кислорода [19]. резистин Резистин -богатый цистеином пептид с молекулярной массой 12,5 кДа.…”