Our previous work indicated exposure of Human liver cell 7702 (HL7702) cells to Microcystin‐leucine‐arginine (MC‐LR) for 24 hours can disrupt insulin (INS) signaling by the hyperphosphorylation of specific proteins. For further exploring the time‐dependent effect posed by MC‐LR on this pathway, in the current study, HL7702 cells together with mice were exposed to the MC‐LR with different concentrations under short‐term treatment, and then, protein phosphatase 2A (PP2A) activity and expression of proteins related to INS signaling, as well as the characteristics of their action in the liver, were investigated. The results indicated, in HL7702 cells with 0.5, 1, and 6 hours of treatment by MC‐LR, PP2A activity showed an obvious decrease in a time and concentration‐dependent manner. While the total protein level of Akt, glycogen synthase kinase 3 (GSK‐3), and glycogen synthase remained unchanged, GSK‐3 and Akt phosphorylation increased significantly. In livers of mice with 1 hour of intraperitoneal injection with MC‐LR, a similar change in these proteins was observed. In addition, the levels of total IRS1 and p‐IRS1 at serine sites showed decreasing and increasing trends,respectively, and the hematoxylin and eosin staining showed that liver tissues of mice in the maximum‐dose group exhibited obvious hepatocyte degeneration and hemorrhage. Our results further proved that short‐term treatment with MC‐LR can inhibit PP2A activity and disrupt INS signaling proteins' phosphorylation level, thereby interfering with the INS pathway. Our findings provide a helpful understanding of the toxic effects posed by MC‐LR on the glucose metabolism of liver via interference with the INS signaling pathway.

中文翻译：

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微囊藻毒素-LR 短期治疗对 HL7702 细胞系和小鼠肝脏胰岛素通路的影响

我们之前的工作表明，将人肝细胞 7702 (HL7702) 细胞暴露于微囊藻毒素-亮氨酸-精氨酸 (MC-LR) 24 小时可以通过特定蛋白质的过度磷酸化破坏胰岛素 (INS) 信号传导。为了进一步探索MC-LR对该通路的时间依赖性影响，在目前的研究中，HL7702细胞与小鼠一起在短期处理下暴露于不同浓度的MC-LR，然后是蛋白磷酸酶2A（ PP2A) 活性和与 INS 信号相关的蛋白质的表达，以及它们在肝脏中的作用特征，进行了研究。结果表明，在 HL7702 细胞中，MC-LR 处理 0.5、1 和 6 小时后，PP2A 活性呈时间和浓度依赖性明显下降。而 Akt 的总蛋白水平，糖原合酶激酶 3 (GSK-3) 和糖原合酶保持不变，GSK-3 和 Akt 磷酸化显着增加。在腹腔注射 MC-LR 1 小时的小鼠肝脏中，观察到这些蛋白质的类似变化。此外，丝氨酸位点总IRS1和p-IRS1水平分别呈下降和上升趋势，苏木精和伊红染色显示最大剂量组小鼠肝组织出现明显的肝细胞变性和出血。我们的研究结果进一步证明，用 MC-LR 短期处理可以抑制 PP2A 活性并破坏 INS 信号蛋白的磷酸化水平，从而干扰 INS 通路。