Pioglitazone Promotes Survival and Prevents Hepatic Regeneration Failure After Partial Hepatectomy in Obese and Diabetic KK-Ay Mice
Pioglitazone Promotes Survival and Prevents Hepatic Regeneration Failure After Partial Hepatectomy in Obese and Diabetic KK-Ay Mice
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DOI：
10.1002/hep.22828
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发表时间：
2009-05-01
期刊：
影响因子：
13.5
通讯作者：
Watanabe, Sumio
中科院分区：
文献类型：
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作者：
Aoyama, Tomonori;Ikejima, Kenichi;Watanabe, Sumio
代谢综合征相关的非酒精性脂肪性肝炎（NASH）的发病机制涉及肝脏中异常的组织修复反应。我们研究了吡格列酮（一种噻唑烷二酮衍生物，TZD）对肥胖的糖尿病KK - A(y)小鼠肝脏再生反应的影响。出生9周的雄性KK - A(y)小鼠在连续5天胃内注射吡格列酮（25mg/kg）后进行了三分之二肝部分切除术（PH）。几乎一半的KK - A(y)小鼠在肝部分切除术后48小时内死亡；然而，用吡格列酮预处理的小鼠死亡率完全得到预防。在KK - A(y)小鼠中，肝部分切除术后48小时溴脱氧尿苷（BrdU）掺入肝细胞核的比例仅为1%；然而，吡格列酮预处理显著将BrdU阳性细胞增加到8%。在KK - A(y)小鼠肝部分切除术后48小时内几乎检测不到细胞周期蛋白D1。相比之下，在吡格列酮预处理的KK - A(y)小鼠中，肝部分切除术后24小时观察到细胞周期蛋白D1明显表达。KK - A(y)小鼠肝部分切除术后1小时肝脏肿瘤坏死因子α（TNF - α）信使核糖核酸（mRNA）大幅增加，其水平比进行肝部分切除术的C57B1/6小鼠高9倍，而吡格列酮使这种增加减弱了近四分之三。吡格列酮几乎完全纠正了KK - A(y)小鼠的低脂联素血症。KK - A(y)小鼠肝部分切除术后24小时血清白细胞介素（IL）- 6和瘦素水平大幅升高，而给予吡格列酮的KK - A(y)小鼠这些水平大幅降低。实际上，吡格列酮阻止了KK - A(y)小鼠肝脏中信号转导和转录激活因子（STAT）3磷酸化以及细胞因子信号抑制因子（SOCS）- 3 mRNA的异常增加。结论：这些发现表明吡格列酮改善了KK - A(y)小鼠的肝脏再生失败。吡格列酮对再生失败产生影响的潜在机制很可能涉及在肝部分切除术后早期脂肪因子表达模式的正常化以及随后的细胞因子反应。（《肝脏病学》2009年；49卷：1636 - 1644页）
Pathogenesis of metabolic syndrome-related nonalcoholic steatohepatitis (NASH) involves abnormal tissue-repairing responses in the liver. We investigated the effect of pioglitazone, a thiazolidinedione derivative (TZD), on hepatic regenerative responses in obese, diabetic KK-A(y) mice. Male KK-A(y) mice 9 weeks after birth underwent two-thirds partial hepatectomy (PH) after repeated intragastric injections of pioglitazone (25 mg/kg) for 5 days. Almost half of the KK-A(y) mice died within 48 hours of PH; however, mortality was completely prevented in mice pretreated with pioglitazone. In KK-A(y) mice, bromodeoxyuidine (BrdU) incorporation to hepatocyte nuclei 48 hours after PH reached only 1%; however, pioglitazone pretreatment significantly increased BrdU-positive cells to 8%. Cyclin D1 was barely detectable in KK-A(y) mice within 48 hours after PH. In contrast, overt expression of cyclin D1 was observed 24 hours after PH in KK-A(y) mice pretreated with pioglitazone. Hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) was tremendously increased 1 hour after PH in KK-A(y) mice, the levels reaching ninefold over C57B1/6 given PH, whereas pioglitazone blunted this increase by almost three-fourths. Pioglitazone normalized hypoadiponectinemia in KK-A(y) mice almost completely. Serum interleukin (IL)-6 and leptin levels were elevated extensively 24 hours after PH in KK-A(y) mice, whereas the levels were largely decreased in KK-A(y) mice given pioglitazone. Indeed, pioglitazone prevented aberrant increases in signal transducers and activators of transcription (STAT)3 phosphorylation and suppressor of cytokine signaling (SOCS)-3 mRNA in the liver in KK-A(y) mice. Conclusion: These findings indicated that pioglitazone improved hepatic regeneration failure in KK-A(y) mice. The mechanism underlying the effect of pioglitazone on regeneration failure most likely involves normalization of expression pattern of adipokines and subsequent cytokine responses during the early stage of PH. (HEPATOLOGY 2009; 49:1636-1644.)