comprehensive study on the mechanisms of liver regeneration toward clinical molecular targeting therapy

肝脏再生是由一系列复杂的过程组成的。本研究旨在通过肝脏特异性STAT3敲除（L-S3KO）、PDK1敲除（L-Pdk1KO）和PDK1/ STAT3双KO （L-DKO）小鼠，研究Jak/STAT3和PDK1/akt相关通路在部分肝切除术（PH）后肝脏再生中的作用。1) LS3-KO小鼠PH后肝细胞增殖明显受到抑制，cyclinD1转录降低。然而，LS3-KO小鼠在PH后肝脏质量恢复充分，与对照组几乎相等。肝切除术后LS3-KO小鼠的细胞大小明显大于对照组小鼠。肝切除术在LS3-KO小鼠中诱导Akt、p70S6K、mTOR和GSK-3b的立即但短暂磷酸化的程度远高于对照小鼠。此外，腺病毒转染Akt显性阴性突变体到对照组和LS3-KO小鼠，导致肝切除术后肝脏再生不足。2) 70%的PH对L-Pdk1KO小鼠有致死性，其余小鼠无肝再生。即使在非致死性30% ph下，L-Pdk1KO和L-DKO小鼠的肝脏再生也同样严重受损。细胞大小的测量显示，L-Pdk1KO小鼠在肝切除术后根本没有发生细胞生长，尽管ph后的有丝分裂反应与对照肝脏的有丝分裂反应程度相同。在L-Pdk1KO小鼠中，ph后Akt、mTOR、p70^<56K>和S6的磷酸化水平也降低。通过在L-Pdk1KO小鼠中引入PDK1的“pif-pocket”突变体来重新激活Akt，可导致ph后肝脏中正常的肝脏再生和细胞生长，而不影响细胞增殖。激活L-Pdk1KO小鼠肝脏中的Pl3-K通过STAT3激活增加了有丝分裂细胞，但根本没有改善L-Pdk1KO小鼠受损的肝脏再生。综上所述，这些事实表明Pl3-K和PDK1/Akt分别通过调节细胞增殖和大小来促进肝脏再生。PDK1/ akt介导的反应性细胞生长在PH后的正常肝脏再生中至关重要，特别是当细胞增殖受损时。少

Liver regeneration is composed of a series of complicated processes. The present study was designed to investigate the roles of Jak/STAT3 and PDK1/akt-associated pathways in liver regeneration following partial hepatectomy (PH) using liver-specific STAT3-knockout (L-S3KO), Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice.1) Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3b in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy.2) 70% PH was lethal in L-Pdk1KO mice with … More no liver regeneration. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice even after non-lethal 30% PH. Measurement of cell size revealed that cell growth following hepatectomy did not occur at all in L-Pdk1KO mice, though post-PH mitotic response occurred to the same degree to the control liver. In L-Pdk1KO mice, post-PH phosphorylation of Akt, mTOR, p70^<56K> and S6 were also reduced.Re-activation of Akt by introducing 'pif-pocket' mutant of PDK1 in L-Pdk1KO mice lead normal liver regeneration and cell growth in the post-PH liver without affecting cell proliferation. Activation of Pl3-K in the liver of L-Pdk1KO mice increased mitotic cells via STAT3 activation, but did not improve impaired liver regeneration in L-Pdk1KO mice at all. Taken together, these facts indicate that Pl3-K and PDK1/Akt contribute to liver regeneration by regulating cell proliferation and size, respectively. PDK1/Akt-mediated responsive cell growth is essential in normal liver regeneration following PH especially when cell proliferation is impaired. Less