Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 22, Pages -Publisher
MDPI
DOI: 10.3390/ijms222212589
Keywords
autophagy; ER stress; hepatocyte; inflammasomes; leptin
Funding
- Basic Science Research Program of the National Research Foundation (NRF) of Korea, funded by the Ministry of Education [NRF-2021R1A2C1013132]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2020R1A6A1A03044512]
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Leptin induces cytotoxicity in rat hepatocytes by activating NLRP3 inflammasomes, mediated through ROS production, ER stress, and autophagy. Inhibition of inflammasomes protects hepatocytes from leptin-induced cell death.
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-1 beta 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.
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