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Role of hypoxia inducible factor-1α in the regulation of hypoxic responses in liver.

缺氧诱导因子-1α在肝脏缺氧反应调节中的作用。

基本信息

批准号：
15390384
负责人：
SHIMAZU Motohide
金额：
$ 3.71万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Mammalian cells have evolved to utilize molecular oxygen for energy production. Cells can respond differentially to wide ranges of oxygen concentrations through activation of varied transcriptional factors. Among them, hypoxia inducible transcription factor HIF-1 is a major regulator of hypoxic responses. This study aimed to elucidate the molecular mechanisms by which hepatic parenchymal cells adapt to hypoxic stress. To this end, we generated mice harboring a floxed HIF-1α allele, and employed the albumin-Cre transgenic line to inactivate HIF-1α gene specifically in hepatocytes. This allowed mice to escape from embryonic lethality and delete HIF-1α gene exclusively in hepatocytes. Histochemical analyses showed that distances between terminal central venule and its closest portal vessel in HIF-1α deficient livers were longer than those in wild type by 50μm. However, expressions of glycolytic enzymes, most of which are known to be regulated by HIF-1 under hypoxia and predominantly present in the pericentral regions of liver, were not disturbed by inactivation of HIF-1α gene. We next subjected mice to 70% partial hepatectomy (PH) to introduce molecular signals to regenerate. Animals were sacrificed at intervals after the surgery, and the remnant liver was harvested and analyzed. We found that regenerating processes in the mutant mice were retarded during the early post-operative periods compared to those observed in the control mice. Moreover, cyclin-dependent kinases and several cell cycle regulators were affected, resulting in inefficient G1-S phase progression. The present study suggests that HIF-1 serves as a putative regulator for liver regeneration.

哺乳动物细胞已经进化到利用分子氧来产生能量。通过激活不同的转录因子，细胞可以对各种氧浓度做出不同的反应。其中，缺氧诱导转录因子HIF-1是缺氧反应的主要调节因子。本研究旨在阐明肝实质细胞适应低氧应激的分子机制。为此，我们培育了携带 floxed HIF-1α 等位基因的小鼠，并采用白蛋白-Cre 转基因系来特异性灭活肝细胞中的 HIF-1α 基因。这使得小鼠能够逃脱胚胎致死并仅删除肝细胞中的 HIF-1α 基因。组织化学分析表明，HIF-1α缺陷型肝脏的终末中央小静脉与其最近的门脉血管之间的距离比野生型长50μm。然而，已知大多数糖酵解酶在缺氧条件下受 HIF-1 调节，并且主要存在于肝脏的中央周围区域，但这些酶的表达并未因 HIF-1α 基因的失活而受到干扰。接下来，我们对小鼠进行 70% 部分肝切除术 (PH)，以引入分子信号进行再生。手术后每隔一段时间处死动物，收获剩余肝脏并进行分析。我们发现，与对照小鼠中观察到的情况相比，突变小鼠的再生过程在术后早期被延迟。此外，细胞周期蛋白依赖性激酶和多种细胞周期调节因子受到影响，导致 G1-S 期进展效率低下。目前的研究表明 HIF-1 是肝脏再生的假定调节因子。