Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of CCl₄. However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl₄. Remarkably, most IGF-2-expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase–deficient mice or in CCl₄ chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF-2 overexpression, which could be inhibited by adeno-associated virus–delivered IGF-2 short hairpin RNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 through both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. Conclusion: IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post-PHx. (Hepatology 2017;66:2002–2015)

中文翻译：

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小鼠外周肝细胞产生胰岛素样生长因子-2，促进小鼠选择性损伤期间的肝再生

各种类型的伤害后会发生肝再生（LR）。与经过充分研究的由部分肝切除术（PHx）引起的LR不同，有越来越多的证据表明，其他损伤期间的LR可能是由未知的机制引起的。在这项研究中，我们发现胰岛素样生长因子2（IGF-2）在酪氨酸血症或CCl ₄长期治疗引起的肝损伤后被急剧诱导。但是，在PHx或CCl ₄单次治疗后急性肝损伤的早期阶段未观察到此现象。值得注意的是，大多数在表达富马酸乙酰乙酸酯水解酶的小鼠或CCl ₄引起的肝损伤后，大多数表达IGF-2的肝细胞都位于肝小叶中央静脉周围的组织学区域。长期治疗的小鼠。诱导的IGF-2过度表达可显着促进体内肝细胞增殖，而腺相关病毒传递的IGF-2短发夹RNA或linsitinib（IGF-2信号抑制剂）可抑制这种表达。体内增殖的肝细胞通过胰岛素受体和IGF-1受体对IGF-2产生反应。IGF-2还可以显着促进体外原代肝细胞DNA的合成。更有趣的是，对于来自肝纤维化患者的肝样品，还发现了显着诱导的IGF-2与谷氨酰胺合成酶共定位在富含增殖肝细胞的区域中。结论：在慢性肝损伤的情况下，IGF-2由中央周围肝细胞产生，以促进肝细胞增殖并修复组织损伤，这与PHx后发生的信号不同。（肝病学2017; 66：2002–2015）