Shan-Shan Lai1, Dan-Dan Zhao1, Peng Cao2, Ke Lu1, Ou-Yang Luo1, Wei-Bo Chen3, Jia Liu1, En-Ze Jiang1, Zi-Han Yu1, Gina Lee4, Jing Li4, De-Cai Yu5, Xiao-Jun Xu6, Min-Sheng Zhu1, Xiang Gao7, Chao-Jun Li8, Bin Xue9. 1. State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. 2. Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Chinese Medicine, Nanjing 210028, China. 3. State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210093, China. 4. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. 5. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210093, China. 6. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. 7. State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. Electronic address: gaoxiang@nju.edu.cn. 8. State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. Electronic address: licj@nju.edu.cn. 9. State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. Electronic address: xuebin@nju.edu.cn.
Abstract
BACKGROUND & AIMS: Liver injury triggers a highly organized and ordered liver regeneration (LR) process. Once regeneration is complete, a stop signal ensures that the regenerated liver is an appropriate functional size. The inhibitors and stop signals that regulate LR are unknown, and only limited information is available about these mechanisms. METHODS: A 70% partial hepatectomy (PH) was performed in hepatocyte-specific PP2Acα-deleted (PP2Acα(-/-)) and control (PP2Acα(+/+)) mice. LR was estimated by liver weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed. RESULTS: We found that the catalytic subunit of PP2A was markedly upregulated during the late stage of LR. PP2Acα(-/-) mice showed prolonged LR termination, an increased liver size compared to the original mass and lower levels of serum ALT and AST compared with control mice. In these mice, cyclin D1 protein levels, but not mRNA levels, were increased. Mechanistically, AKT activated by the loss of PP2Acα inhibited glycogen synthase kinase 3β (GSK3β) activity, which led to the accumulation of cyclin D1 protein and accelerated hepatocyte proliferation at the termination stage. Treatment with the PI3K inhibitor wortmannin at the termination stage was sufficient to inhibit cyclin D1 accumulation and hepatocyte proliferation. CONCLUSIONS: PP2Acα plays an essential role in the proper termination of LR via the AKT/GSK3β/Cyclin D1 pathway. Our findings enrich the understanding of the molecular mechanism that controls the termination of LR and provides a potential therapeutic target for treating liver injury.
BACKGROUND & AIMS:Liver injury triggers a highly organized and ordered liver regeneration (LR) process. Once regeneration is complete, a stop signal ensures that the regenerated liver is an appropriate functional size. The inhibitors and stop signals that regulate LR are unknown, and only limited information is available about these mechanisms. METHODS: A 70% partial hepatectomy (PH) was performed in hepatocyte-specific PP2Acα-deleted (PP2Acα(-/-)) and control (PP2Acα(+/+)) mice. LR was estimated by liver weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed. RESULTS: We found that the catalytic subunit of PP2A was markedly upregulated during the late stage of LR. PP2Acα(-/-) mice showed prolonged LR termination, an increased liver size compared to the original mass and lower levels of serum ALT and AST compared with control mice. In these mice, cyclin D1 protein levels, but not mRNA levels, were increased. Mechanistically, AKT activated by the loss of PP2Acα inhibited glycogen synthase kinase 3β (GSK3β) activity, which led to the accumulation of cyclin D1 protein and accelerated hepatocyte proliferation at the termination stage. Treatment with the PI3K inhibitor wortmannin at the termination stage was sufficient to inhibit cyclin D1 accumulation and hepatocyte proliferation. CONCLUSIONS: PP2Acα plays an essential role in the proper termination of LR via the AKT/GSK3β/Cyclin D1 pathway. Our findings enrich the understanding of the molecular mechanism that controls the termination of LR and provides a potential therapeutic target for treating liver injury.