Heat shock protein 70 is required for optimal liver regeneration after partial hepatectomy in mice.
Heat shock protein 70 is required for optimal liver regeneration after partial hepatectomy in mice.
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DOI：
10.1002/lt.23813
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
Levine MH
中科院分区：
文献类型：
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作者：
Wolf JH;Bhatti TR;Fouraschen S;Chakravorty S;Wang L;Kurian S;Salomon D;Olthoff KM;Hancock WW;Levine MH
肝再生是一个复杂的过程，在切除或损伤后恢复功能组织，并伴随着短暂的ATP耗竭和肝实质细胞的代谢应激。热休克蛋白-70（Hsp 70）在细胞应激期间起伴侣作用，并诱导几种炎症细胞因子的表达，这些细胞因子在早期肝再生过程中被鉴定为关键参与者。因此，我们推测，热休克蛋白70将需要在再生的启动。在70%部分肝切除（PHx）小鼠模型中进行了研究，小鼠缺乏诱导型Hsp 70（Hsp 70 −/−）。术后使用肝脏重量与体重的比值（LW/BW）评估肝再生，并收集血清和组织进行分析。此外，在23名人类活体肝移植供体的队列中评估了Hsp相关基因的基因表达。在小鼠中，与野生型小鼠相比，缺乏Hsp 70与术后LW/BW、Ki-67染色和TNF-α表达降低相关。LPS（1 mg/kg）诱导后，Hsp 70 −/−小鼠肝脏中的TNF-α表达也降低。临床上，多个Hsp基因的转录上调后供体肝切除术，特别是Hsp 70家族成员。总之，这些结果表明，成功的肝再生的早期阶段需要Hsp 70的存在来诱导TNF-α。需要进一步的研究，以确定是否热休克蛋白70有助于肝再生的伴侣，通过稳定特定的相互作用所需的生长信号，或作为旁分泌炎症信号，可以发生在休克模型。
Liver regeneration is a complex process that restores functional tissue following resection or injury, and is accompanied by transient ATP depletion and metabolic stress in hepatic parenchymal cells. Heat shock protein-70 (Hsp70) functions as a chaperone during periods of cellular stress, and induces expression of several inflammatory cytokines identified as key players during early liver regeneration. We therefore hypothesized that Hsp70 would be required in the initiation of regeneration. Investigations were carried out in a 70% partial-hepatectomy (PHx) mouse model with mice lacking inducible Hsp70 (Hsp70−/−). Liver regeneration was assessed post-operatively using the ratio of liver weight to body weight (LW/BW), and sera and tissues were collected for analysis. In addition, gene expression of Hsp related genes were assessed in a cohort of 23 human living-donor liver transplantation donors. In mice, the absence of Hsp70 was associated with reduced postoperative LW/BW, Ki-67 staining, and TNF-α expression compared to wild-type mice. TNF-α expression was also reduced in livers from Hsp70−/− mice following induction with LPS (1 mg/kg). Clinically, the transcription of multiple Hsp genes was upregulated following donor hepatectomy, especially Hsp70 family members. Together, these results suggest that the early phase of successful liver regeneration requires the presence of Hsp70 to induce TNF-α. Further studies are required to determine whether Hsp70 contributes to liver regeneration as a chaperone, by stabilizing specific interactions required for growth signalling, or as a paracrine inflammatory signal, as can occur in models of shock.