Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy
Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy
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DOI：
10.1007/s00423-012-0998-5
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发表时间：
2012-12-01
影响因子：
2.3
通讯作者：
Schneider, Martin
中科院分区：
文献类型：
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作者：
Mollenhauer, Martin;Kiss, Judit;Schneider, Martin
肝部分切除(PH)后的肝脏再生发生在氧气供应减少的情况下。HIF脯氨酸羟基酶(PhD1、PHD2和PHD3)是参与低氧适应反应的氧感受器。然而，这些PHD酶在肝脏再生中的具体功能仍然是个谜。在这里，我们研究了Phd1基因在肝切除后肝再生中的意义。我们研究了Phd1基因缺陷(Phd1(-/-))和野生型(WT)小鼠接受80%肝切除后的肝再生。为了进行体外分析，从PhD1(-/-)和WT肝脏中分离出肝细胞。通过基于FACS的核DNA图谱分析来研究细胞周期进程。应用转录因子结合分析、qRT-PCR和免疫印迹等方法研究肝再生过程中phd1下游效应因子的相关性。与WT仔鼠相比，phd1(-/-)小鼠的肝再生显著增强。这种效应是由于促进了肝细胞的增殖，而不是由于肝细胞的肥大。在PhD1缺陷的肝细胞中，细胞周期进程显著增强，细胞周期调节因子c-Myc的转录活性增加。这些变化与促进细胞周期的c-Myc靶标细胞周期蛋白D2的表达增加和延迟细胞周期的c-Myc靶标p21的表达减少相一致。PhD1的缺失通过促进c-Myc依赖的方式促进肝细胞的增殖来促进肝再生。因此，PhD1可能是促进手术切除后肝再生的潜在靶点。
Liver regeneration after partial hepatectomy (PH) occurs in conditions of reduced oxygen supply. HIF prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) are oxygen sensors involved in adaptive response to hypoxia. Specific functions of these PHD enzymes in liver regeneration have, however, remained enigmatic. Here, we investigated the significance of PHD1 in liver regeneration following hepatectomy.Liver regeneration was studied in PHD1-deficient (PHD1(-/-)) and wild type (WT) mice subjected to 80 % hepatectomy. For in vitro analyses, hepatocytes were isolated from PHD1(-/-) and WT livers. Cell cycle progression was studied via FACS-based analysis of nuclear DNA profile. Transcription factor binding assays, qRT-PCR, and immunoblotting were applied to study the relevance of PHD1 downstream effectors during liver regeneration.Liver regeneration was significantly enhanced in PHD1(-/-) mice compared to WT littermates. This effect was due to enhanced proliferation rather than to hypertrophy of liver cells. Cell cycle progression was significantly enhanced, and transcriptional activity of the cell cycle regulator c-Myc was increased in PHD1-deficient hepatocytes. These changes coincided with increased expression of cyclin D2, a cell cycle-promoting c-Myc target, and decreased expression of the cell cycle-delaying c-Myc target p21.Loss of PHD1 enhances liver regeneration by boosting hepatocyte proliferation in a c-Myc-dependent fashion. PHD1 might, therefore, represent a potential target to facilitate liver regeneration after surgical resection.