The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Medical School and Model Animal Research Center of Nanjing University, Nanjing, China.
Biochem Biophys Res Commun. 2020 May 21;526(1):1-7. doi: 10.1016/j.bbrc.2020.03.002. Epub 2020 Mar 16.
The mechanisms underlying the initiation and proliferation of liver regeneration (LR) has been extensively studied using the partial hepatectomy (PHx) model, while little is known about the termination of LR. PP2Acα (protein phosphatase 2 A catalytic subunit α isoform) is the catalytic subunit of protein phosphatase 2 A (PP2A), accounting for most of intracellular serine/threonine phosphatase activity. We have previously observed that termination of LR delayed in PP2Acα liver-specific knockout (LKO) mice after PHx. In our study, we used phospho explorer antibody array analysis to screen the potential phosphorylation targets of PP2Acα, and PP2Acα had a great influence on the hepatic phosphoproteomic signaling in the termination of LR after PHx. We then tested the phosphorylation changes and metabolic function of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2 (PFKFB2), an isoform of the key glycolytic enzyme PFKFB, which was significantly regulated by PP2Acα knockout. PP2Acα knockout enhanced glycolysis in vivo and in vitro, while adenoviral-mediated RNAi of PFKFB2 reversed the extension of postoperative liver regeneration in KO mice along with the downregulation of glycolysis. Therefore, we demonstrated that PP2Acα liver-specific knockout regulated the hepatocytes glycolysis via activating PFKFB2, thus enhancing liver regeneration during the termination stage.
肝再生（LR）的启动和增殖的机制已在使用部分肝切除术（PHx）模型中进行了广泛研究，而对于 LR 的终止知之甚少。PP2Acα（蛋白磷酸酶 2A 催化亚基α同工型）是蛋白磷酸酶 2A（PP2A）的催化亚基，占细胞内丝氨酸/苏氨酸磷酸酶活性的大部分。我们之前观察到，在 PHx 后，PP2Acα 肝特异性敲除（LKO）小鼠的 LR 终止延迟。在我们的研究中，我们使用磷酸化探索者抗体阵列分析筛选 PP2Acα 的潜在磷酸化靶标，并且 PP2Acα 对 PHx 后 LR 终止时的肝磷酸蛋白组学信号有很大影响。然后，我们测试了 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-2（PFKFB2）的磷酸化变化和代谢功能，PFKFB2 是关键糖酵解酶 PFKFB 的同工型，其受到 PP2Acα 敲除的显著调节。PP2Acα 敲除增强了体内和体外的糖酵解，而腺病毒介导的 PFKFB2 RNAi 逆转了 KO 小鼠术后肝再生的延长以及糖酵解的下调。因此，我们证明了 PP2Acα 肝特异性敲除通过激活 PFKFB2 调节肝细胞糖酵解，从而在终止阶段增强肝再生。
