STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers
STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers
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DOI：
10.1016/s0002-9440(10)64167-3
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发表时间：
2002-07-01
影响因子：
6
通讯作者：
Diehl, AM
中科院分区：
文献类型：
--
作者：
Torbenson, M;Yang, SQ;Diehl, AM
脂肪肝是人类发病的一个重要原因，并与肝损伤后肝再生受损有关，但肝再生受损的机制尚不清楚。在正常肝脏中，IL-6/STAT-3途径被认为在再生中起核心作用，因为在IL-6缺乏的小鼠中，这一途径被破坏，这些小鼠在70%肝部分切除(PH)后表现出肝再生受损。为了确定STAT-3的抑制是否与脂肪肝相关的有丝分裂抑制有关，我们比较了正常小鼠和瘦素缺乏的ob/ob小鼠的再生诱导，这些小鼠有脂肪肝，而且PH后肝再生明显受损。两组均观察到两波STAT-3激活，第一波在血管内皮细胞，第二波在肝细胞。PH前，ob/ob内皮细胞和肝细胞核表达磷酸化(活化)的STAT-3的百分比明显较高。PH后，瘦小鼠肝细胞核中磷酸化STAT-3积聚，这种反应在ob/ob小鼠中明显夸大。此外，肝细胞核内磷酸化STAT-3的积聚与DNA合成(用溴脱氧尿嘧啶核苷标记)、细胞周期蛋白DIm RNA的诱导和蛋白表达呈显著负相关。相反，在两组小鼠中，STAT-3的激活与p21蛋白的表达呈正相关。由于这些结果将夸大的STAT-3激活与肝细胞增殖受损联系在一起，STAT-3的抑制不能成为肥胖/肥胖脂肪肝的生长抑制机制。相反，该因子的过度诱导可能通过上调阻碍细胞周期进程的机制来促进有丝分裂抑制。
Fatty liver is an important cause of morbidity in humans and is linked to impaired liver regeneration after liver injury, but the mechanisms for impaired liver regeneration remain unknown. in the normal liver, the interleukin (IL)-6/STAT-3 pathway is thought to play a central role in regeneration because this pathway is disrupted in IL-6-deficient mice that exhibit impaired liver regeneration after 70% partial hepatectomy (PH). To determine whether inhibition of STAT-3 is involved in fatty liver-related mitoinhibition, regenerative induction of STAT-3 was compared in normal mice and leptin-deficient ob/ob mice that have fatty livers and markedly impaired liver regeneration after PH. In both groups, two waves of STAT-3 activation were observed, the first in endothelia and the second in hepatocytes. Before PH, a significantly higher percentage of ob/ob endothelial and hepatocyte nuclei expressed phosphorylated (activated) STAT-3. After PH, phospho-STAT-3 accumulated in liver nuclei of lean mice and this response was markedly exaggerated in ob/ob mice. Moreover, a striking inverse correlation was noted between hepatocyte nuclear accumulation of phospho-STAT-3 and DNA synthesis (as assessed by bromodeoxyuridine labeling), as well as cyclin D I mRNA induction and protein expression. In contrast, STAT-3 activation was positively correlated with p21 protein expression in both groups of mice. Because these results link exaggerated STAT-3 activation with impaired hepatocyte proliferation, STAT-3 inhibition cannot be a growth-arrest mechanism in ob/ob fatty livers. Rather, hyperinduction of this factor may promote mitoinhibition by up-regulating mechanisms that impede cell cycle progression.