Bach1 Deficiency Ameliorates Hepatic Injury in a Mouse Model
Bach1 Deficiency Ameliorates Hepatic Injury in a Mouse Model
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DOI：
10.1620/tjem.217.223
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发表时间：
2009-03-01
影响因子：
2.2
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Iida, Akio;Inagaki, Koji;Igarashi, Kazuhiko
Bach1是一种基本的区域亮氨酸拉链（bZip）蛋白，与小的Maf蛋白形成异源二聚体，并作为基因表达的抑制因子。Bach1的靶基因之一是编码血红素加氧酶-1 （HO-1）的Hmox-1。HO-1将血红素降解为一氧化碳（CO）、胆绿素和铁。HO-1受各种应激及其底物血红素的强烈诱导，通过反应产物CO和胆绿素的多种细胞保护功能保护细胞和组织免受损伤。小鼠bach1缺乏导致Hmox-1在各组织中的高表达。本研究研究了Bach i缺乏对小鼠组织损伤的影响：d -半乳糖胺（GalN）和脂多糖（LPS）诱导的肝损伤，以及各种海藻提取的多糖角叉菜胶（carrageenin）诱导的小鼠足水肿。在GalN/ lps处理下，bach1缺乏抑制了血浆丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）活性的诱导。然而，作为lps诱导肝损伤的细胞毒性介质，肿瘤坏死因子α (tnf - α)和一氧化氮（NO）的产生在bach1缺陷小鼠及其腹膜巨噬细胞中与野生型对照组相似。相反，bach1缺乏不影响卡拉胶素引起的小鼠足部水肿程度，卡拉胶素通过激活激肽释放来增强血管通透性。这些结果表明，Bach1在lps诱导的肝损伤的细胞保护中起抑制作用，而在激肽介导的炎性水肿中不起抑制作用。Bach1的抑制作用可能源于其抑制HO-1等基因的表达。
Bach1 is a basic region-leucine zipper (bZip) protein that forms heterodimers with the small Maf proteins and functions as a repressor of gene expression. One of the target genes of Bach1 is Hmox-1 that encodes heme oxygenase-1 (HO-1). HO-1 degrades heme into carbon monoxide (CO), biliverdin, and iron. HO-1 is strongly induced by various stresses as well as its substrate heme, and protects cells and tissues against insults through diverse cytoprotective functions of the reaction products CO and biliverdin. Bach1-deficiency in mice leads to higher expression of Hmox-1 in various tissues. Here we investigated the effects of Bach I-deficiency in mice on tissue injuries: hepatic injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS), and mouse paw edema induced by carrageenin, polysaccharide derived from various seaweeds. Bach1-deficiency suppressed induction of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in response to the GalN/LPS-treatment. However, production of tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO), both being cytotoxic mediators in LPS-induced hepatic injury, in Bach1-deficient mice and their peritoneal macrophages was similar to wild type controls. In contrast, Bach1-deficiency did not affect extent of mouse paw edema induced by carrageenin, which enhances vascular permeability by activating kinin release. These results indicate that Bach1 plays an inhibitory role in the cytoprotection of LPS-induced liver injury but not in the kinin-mediated inflammatory edema. The inhibitory role for Bach1 may stem from its activity to repress gene expression including HO-1.