与急性肝损伤后的强大增殖相比，肝细胞在慢性肝损伤中表现出长期的增殖活动。这些不同增殖模式之间的机制差异尚不清楚。肝细胞在小鼠部分肝切除后的2天内表现出强大的增殖，但该增殖被肝细胞特异性表达的Myc亚家族抑制融合蛋白完全抑制。然而，Myc的抑制引起了弱但持续的肝细胞增殖，从而在最初的延迟部分恢复了肝脏质量。出现较晚的增殖伴随着脯氨酸脱氢酶（PRODH）表达的长期抑制，并且强制表达PRODH会抑制肝细胞增殖。在慢性肝损伤中的肝细胞中，Myc未被激活，但产生大量的PRODH表达。在肝癌中，PRODH的表达通常被抑制，特别是在表达Myc的高增殖性肿瘤中。我们的结果表明，急性肝损伤后肝细胞的强大增殖需要高水平的Myc表达，并且还存在一种代偿性的Myc独立型肝细胞增殖模式，其调节脯氨酸代谢可能与慢性损伤中的肝脏再生相关。版权所有©2023 Elsevier B.V.发表。

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.Copyright © 2023. Published by Elsevier B.V.