High levels of Myc expression are required for the robust proliferation of hepatocytes, but not for the sustained weak proliferation
High levels of Myc expression are required for the robust proliferation of hepatocytes, but not for the sustained weak proliferation
复制标题
高水平的Myc表达对于肝细胞的旺盛增殖是必需的，但对于持续的弱增殖则不需要
DOI：
10.1016/j.bbadis.2023.166644
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Nishikawa Yuji
中科院分区：
文献类型：
--
作者：
Goto Masanori;Ooshio Takako;Yamamoto Masahiro;Tanaka Hiroki;Fujii Yumiko;Meng Lingtong;Kamikokura Yuki;Okada Yoko;Nishikawa Yuji
与急性肝损伤后表现出的强劲增殖相反，肝细胞在慢性肝损伤中表现出持久的增殖活性。这些不同的增殖模式之间的机制差异尚不清楚。肝细胞表现出强劲的增殖，在小鼠部分肝切除术后2天达到峰值，但这种增殖完全抑制肝细胞特异性表达的MadMyc，Myc抑制嵌合蛋白。然而，Myc抑制诱导弱但持续的肝细胞增殖，从而导致肝脏质量的完全恢复，尽管最初的延迟。晚期发生的增殖伴随着脯氨酸脱氢酶（PRODH）表达的长期抑制，并强制PRODH过表达抑制肝细胞增殖。在慢性肝损伤的肝细胞中，Myc未被激活，但PRODH表达在再生肝细胞中被抑制。在肝肿瘤中，PRODH表达通常被抑制，特别是在具有不同Myc表达的高度增殖性肿瘤中。我们的研究结果表明，急性肝损伤后肝细胞的稳健增殖需要高水平的Myc表达，并且存在一种补偿性的Myc非依赖性的肝细胞增殖模式，其调节脯氨酸代谢，这可能与慢性损伤中的肝再生有关。
In contrast to the robust proliferation exhibited following acute liver injury, hepatocytes exhibit long-lasting proliferative activity in chronic liver injury. The mechanistic differences between these distinct modes of proliferation are unclear. Hepatocytes exhibited robust proliferation that peaked at 2 days following partial hepatectomy in mice, but this proliferation was completely inhibited by hepatocyte-specific expression of MadMyc, a Myc-suppressing chimeric protein. However, Myc suppression induced weak but continuous hepatocyte proliferation, thereby resulting in full restoration of liver mass despite an initial delay. Late-occurring proliferation was accompanied by prolonged suppression of proline dehydrogenase (PRODH) expression, and forced PRODH overexpression inhibited hepatocyte proliferation. In hepatocytes in chronic liver injury, Myc was not activated but PRODH expression was suppressed in regenerating hepatocytes. In liver tumors, PRODH expression was often suppressed, especially in the highly proliferative tumors with distinct Myc expression. Our results indicate that the robust proliferation of hepatocytes following acute liver injury requires high levels Myc expression and that there is a compensatory Myc-independent mode of hepatocyte proliferation with the regulation of proline metabolism, which might be relevant to liver regeneration in chronic injury.