AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates D-Gal/LPS-induced liver injury
AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates D-Gal/LPS-induced liver injury
复制标题
AKT 激活剂 SC79 保护肝细胞免受 TNF-α 介导的细胞凋亡并减轻 D-Gal/LPS 诱导的肝损伤
DOI：
10.1152/ajpgi.00350.2018
复制
发表时间：
2019-03-01
影响因子：
4.5
通讯作者：
Lin, Xu
中科院分区：
文献类型：
--
作者：
Jing, Zhen-Tang;Liu, Wei;Lin, Xu
肿瘤坏死因子-α是一种高度多效性的细胞因子，具有多种生物学功能，包括细胞增殖、代谢激活、炎症反应和细胞死亡。肿瘤坏死因子-α可诱导多种机制启动肝细胞的凋亡，从而导致随后的肝损伤。由于磷脂酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)通路在死亡因子介导的细胞凋亡中具有保护作用，我们假设Akt的激活可能是减轻肿瘤坏死因子-α诱导的肝细胞凋亡和肝损伤的一种治疗策略。我们报道Akt激活剂SC79保护肝细胞免受肿瘤坏死因子-α诱导的肝细胞凋亡，并保护D-氨基半乳糖(D-Gal)/脂多糖(LPS)诱导的小鼠免受肿瘤坏死因子-α介导的肝损伤。SC79不仅增强了核因子-kappa B(NF-kappa B)在肿瘤坏死因子-α刺激下的生存信号，而且还上调了细胞内FADD样IL-1β转换酶抑制蛋白L和S(Flip1/S)的表达，从而抑制原天冬氨酸酶-8的激活。此外，PI3K/Akt抑制剂LY294002可逆转SC79诱导的所有肝保护作用。这些结果有力地表明，SC79对肿瘤坏死因子-α诱导的肝细胞凋亡具有保护作用，提示SC79可能是一种有希望的治疗药物，以改善肝损伤的发展。值得注意的新发现和值得注意的SC79保护肝细胞免受肿瘤坏死因子-α诱导的细胞凋亡和保护小鼠免受半乳糖/脂多糖诱导的肝损伤。SC79对肿瘤坏死因子-α的细胞保护作用是通过AKT介导的核因子-kappaB的激活和Flipl/S的上调来实现的。
Tumor necrosis factor-alpha (TNF-alpha) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-alpha can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-alpha-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-alpha-induced apoptosis and protects mice from D-galactosamine (D-Gal)/lipopolysaccharide (LPS)-induced TNF-alpha-mediated liver injury and damage. SC79 not only enhances the nuclear factor-kappa B (NF-kappa B) prosurvival signaling in response to TNF-alpha stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1 beta-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-alpha-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury.NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-alpha-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-alpha act through both AKT-mediated activation of NF-kappa B and upregulation of FLIPL/S.