The Survival Pathways Phosphatidylinositol-3 Kinase (PI3-K)/Phosphoinositide-Dependent Protein Kinase 1 (PDK1)/Akt Modulate Liver Regeneration Through Hepatocyte Size Rather Than Proliferation
The Survival Pathways Phosphatidylinositol-3 Kinase (PI3-K)/Phosphoinositide-Dependent Protein Kinase 1 (PDK1)/Akt Modulate Liver Regeneration Through Hepatocyte Size Rather Than Proliferation
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DOI：
10.1002/hep.22583
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发表时间：
2009-01-01
期刊：
影响因子：
13.5
通讯作者：
Todo, Satoru
中科院分区：
文献类型：
--
作者：
Haga, Sanae;Ozaki, Michitaka;Todo, Satoru
肝再生包括一系列复杂的过程。本研究旨在使用肝脏特异性Pdk 1敲除（L-Pdk 1 KO）和Pdk 1/STAT 3双敲除（L-DKO）小鼠研究磷酸肌醇依赖性蛋白激酶1（PDK 1）相关通路在部分肝切除术（PH）后肝再生中的作用。L-Pdk 1 KO小鼠无肝再生，70%PH致死。肝再生严重受损，同样在L-Pdk 1 KO和L-DKO小鼠，即使在非致死性30%PH。有没有细胞生长（测量为细胞大小的增加）后，肝切除术在L-Pdk 1 KO小鼠，虽然后PH有丝分裂反应是相同的，在对照组。正如预期的那样，肝切除术在L-Pdk 1 KO小鼠中没有诱导肝脏Akt磷酸化（Thr 308），并且Akt、哺乳动物雷帕霉素靶蛋白（mTOR）、p70核糖体S6激酶（P70（S6 K））和S6的PH后磷酸化也减少。为了检查PDK 1相关信号的特定作用，使用了PDK 1的“pif-口袋”突变体，其仅允许PDK 1磷酸化Akt。在具有PDK 1的“pif-口袋”突变体的L-Pdk 1 KO小鼠中恢复了肝再生。这重新激活了L-Pdk 1 KO小鼠肝脏中的Akt，并诱导PH后细胞生长，而不影响细胞增殖。STAT 3的进一步缺失（L-DKO小鼠）不会进一步恶化肝再生，尽管这肯定会降低PH后有丝分裂反应。这些发现表明PDK 1/Akt通过调节细胞大小而有助于肝再生。关于磷脂酰肌醇-3激酶（PI 3-K），PDK 1的直接上游信号，PI 3-K的激活通过L-Pdk 1 KO小鼠肝脏中的STAT 3激活诱导细胞增殖，但没有改善受损的肝再生。这证实了PDK 1在肝再生和细胞生长中的关键作用。结论：PDK 1/Akt介导的响应性细胞生长对于PH后的正常肝再生至关重要，特别是当细胞增殖受损时。（肝脏学2009;49：204-214。）
Liver regeneration comprises a series of complicated processes. The current study was designed to investigate the roles of phosphoinositide-dependent protein kinase 1 (PDK1)-associated pathways in liver regeneration after partial hepatectomy (PH) using liver-specific Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice. There was no liver regeneration, and 70% PH was lethal in L-Pdk1KO mice. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice, even after nonlethal 30% PH. There was no cell growth (measured as increase of cell size) after hepatectomy in L-Pdk1KO mice, although the post-PH mitotic response was the same as in controls. As expected, hepatectomy did not induce hepatic Akt-phosphorylation (Thr308) in L-Pdk1KO mice, and post-PH phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (P70(S6K)), and S6 were also reduced. To examine the specific role of PDK1-associated signals, a "pif-pocket" mutant of PDK1, which allows PDK1 only to phosphorylate Akt, was used. Liver regeneration was recovered in L-Pdk1KO mice with a "pif-pocket" mutant of PDK1. This re-activated Akt in L-Pdk1KO mice liver and induced post-PH cell growth, without affecting cell proliferation. Further deletion of STAT3 (L-DKO mice) did not further deteriorate liver regeneration, although this certainly reduced post-PH mitotic response. These findings indicate that PDK1/Akt contribute to liver regeneration by regulating cell size. Regarding phosphatidylinositol-3 kinase (PI3-K), immediate upstream signal of PDK1, activation of PI3-K induced cell proliferation via STAT3 activation in the liver of L-Pdk1KO mice but did not improve impaired liver regeneration. This confirmed the pivotal role of PDK1 in liver regeneration and cell growth. Conclusion: PDK1/Akt-mediated responsive cell growth is essential for normal liver regeneration after PH, especially when cell proliferation is impaired. (HEPATOLOGY 2009;49:204-214.)