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.
Highlights
Leptin, a hormone that is primarily derived from adipose tissue, possesses diverse and complex metabolic signaling potential, and there is a growing appreciation that elevated plasma leptin levels are related to numerous metabolic disorders [1]
To investigate whether leptin directly exerts cytotoxic effects in hepatocytes, we examined the effect of leptin on the viability of rat hepatocytes
Pretreatment with an IL-1 receptor antagonist (IL-1 RA) blocked leptin-induced caspase-3 activation (Figure 2I) and Lactate Dehydrogenase (LDH) release (Figure 2J). These results collectively indicate that NLRP3 inflammasome activation mediates the cytotoxic effects of leptin in hepatocytes
Summary
A hormone that is primarily derived from adipose tissue, possesses diverse and complex metabolic signaling potential, and there is a growing appreciation that elevated plasma leptin levels are related to numerous metabolic disorders [1]. Leptin activates hepatic stellate cells, which leads to the up-regulation of collagen expression and promotes hepatic fibrosis [2]. It stimulates Kupffer cells, resident macrophages in the liver, leading to inflammatory responses and the development of steatohepatitis [3]. It has been well documented that leptin induces various pathophysiological conditions in the liver by modulating several signaling cascades in different liver cells. It is unclear whether leptin directly causes cytotoxicity in hepatocytes, and the underlying mechanisms are not well defined
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