Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Langenbecks Arch Surg. 2012 Dec;397(8):1313-22. doi: 10.1007/s00423-012-0998-5. Epub 2012 Sep 11.
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.
部分肝切除术（PH）后的肝再生发生在氧供应减少的情况下。低氧诱导因子脯氨酰羟化酶酶（PHD1、PHD2 和 PHD3）是参与低氧适应反应的氧传感器。然而，这些 PHD 酶在肝再生中的特定功能仍然是个谜。在这里，我们研究了 PHD1 在肝切除术后肝再生中的意义。
研究了 PHD1 缺陷（PHD1（-/-））和野生型（WT）小鼠在接受 80%肝切除术后的肝再生情况。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 图谱分析研究细胞周期进程。应用转录因子结合测定、qRT-PCR 和免疫印迹来研究 PHD1 下游效应子在肝再生过程中的相关性。
与 WT 同窝仔相比，PHD1（-/-）小鼠的肝再生明显增强。这种作用是由于细胞增殖增强而不是肝细胞肥大。细胞周期进程明显增强，PHD1 缺陷型肝细胞中细胞周期调节因子 c-Myc 的转录活性增加。这些变化与细胞周期促进剂 c-Myc 靶蛋白 cyclin D2 的表达增加和细胞周期延迟 c-Myc 靶蛋白 p21 的表达减少相一致。
PHD1 的缺失通过依赖 c-Myc 的方式增强肝细胞增殖来增强肝再生。因此，PHD1 可能成为促进手术切除后肝再生的潜在靶点。
