Clinical Medical School, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.
Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing 401331, China.
Int J Med Sci. 2021 Oct 25;18(16):3831-3838. doi: 10.7150/ijms.52011. eCollection 2021.
Fas-induced apoptosis is a central mechanism of hepatocyte damage during acute and chronic hepatic disorders. Increasing evidence suggests that circadian clock plays critical roles in the regulation of cell fates. In the present study, the potential significance of REV-ERBα, a core ingredient of circadian clock, in Fas-induced acute liver injury has been investigated. The anti-Fas antibody Jo2 was injected intraperitoneally in mice to induce acute liver injury and the REV-ERBα agonist GSK4112 was administered. The results indicated that treatment of GSK4112 decreased the level of plasma ALT and AST, attenuated the liver histological changes, and promoted the survival rate in Jo2-insulted mice. Treatment with GSK4112 also downregulated the activities of caspase-3 and caspase-8, suppressed hepatocyte apoptosis. In addition, treatment with GSK4112 decreased the level of Fas and enhanced the phosphorylation of Akt. In conclusion, treatment with GSK4112 alleviated Fas-induced apoptotic liver damage in mice, suggesting that REV-ERBα agonist might have potential value in pharmacological intervention of Fas-associated liver injury.
Fas 诱导的细胞凋亡是急性和慢性肝紊乱期间肝细胞损伤的一个中心机制。越来越多的证据表明，生物钟在细胞命运的调控中起着关键作用。在本研究中，研究了生物钟的核心成分 REV-ERBα 在 Fas 诱导的急性肝损伤中的潜在意义。在小鼠中腹腔内注射抗 Fas 抗体 Jo2 以诱导急性肝损伤，并给予 REV-ERBα 激动剂 GSK4112。结果表明，GSK4112 处理降低了血浆 ALT 和 AST 的水平，减轻了肝组织学变化，并提高了 Jo2 损伤小鼠的存活率。GSK4112 处理还下调了 caspase-3 和 caspase-8 的活性，抑制了肝细胞凋亡。此外，GSK4112 处理降低了 Fas 的水平并增强了 Akt 的磷酸化。总之，GSK4112 处理减轻了 Fas 诱导的小鼠肝损伤中的凋亡，表明 REV-ERBα 激动剂可能在 Fas 相关肝损伤的药物干预中有潜在价值。
