College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Korea.
Int J Mol Sci. 2021 Nov 22;22(22):12589. doi: 10.3390/ijms222212589.
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.
瘦素是一种主要由脂肪组织产生的激素，与各种肝脏疾病密切相关。然而，人们对于瘦素是否直接诱导肝细胞产生细胞毒性以及涉及的机制仍了解甚少。炎症小体是先天免疫系统的关键组成部分，最近研究表明其可以调节细胞死亡。在这项研究中，我们研究了瘦素对大鼠肝细胞活力的影响及其潜在机制，特别关注炎症小体激活的作用。瘦素处理可降低细胞活力、增加半胱天冬酶-3 活性和增强乳酸脱氢酶释放，从而诱导大鼠肝细胞产生细胞毒性。瘦素在体外和体内均可激活 NLRP3 炎症小体，这可通过白细胞介素-1β和半胱天冬酶-1 的成熟以及炎症小体成分（包括 NLRP3 和 ASC）的表达增加来确定。在机制上，瘦素诱导的炎症小体激活是通过 ROS 产生、内质网应激和自噬轴介导的。值得注意的是，用 NLRP3 抑制剂或白细胞介素-1 受体拮抗剂处理可抑制炎症小体，从而保护肝细胞免受瘦素诱导的细胞死亡。综上所述，这些结果表明，瘦素至少部分通过激活 NLRP3 炎症小体对肝细胞产生细胞毒性作用。
