Department of Pharmacology, Toxicology, and Experimental Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Liver Int. 2010 May;30(5):669-82. doi: 10.1111/j.1478-3231.2010.02205.x. Epub 2010 Feb 15.
BACKGROUND/AIMS: During development of liver fibrosis, an important source of myofibroblasts is hepatocytes, which differentiate into myofibroblasts by epithelial to mesenchymal transition (EMT). In epithelial tumours and kidney fibrosis, hypoxia, through activation of hypoxia-inducible factors (HIFs), is an important stimulus of EMT. Our recent studies demonstrated that HIF-1alpha is important for the development of liver fibrosis. Accordingly, the hypothesis was tested that hypoxia stimulates hepatocyte EMT by a HIF-dependent mechanism.
Primary mouse hepatocytes were exposed to room air or 1% oxygen and EMT evaluated. In addition, bile duct ligations (BDLs) were performed in control and HIF-1alpha-deficient mice and EMT quantified.
Exposure of hepatocytes to 1% oxygen increased expression of alpha-smooth muscle actin, vimentin, Snail and fibroblast-specific protein-1 (FSP-1). Levels of E-cadherin and zona occludens-1 were decreased. Upregulation of FSP-1 and Snail by hypoxia was completely prevented in HIF-1beta-deficient hepatocytes and by pretreatment with SB431542, a transforming growth factor-beta (TGF-beta) receptor inhibitor. HIFs promoted TGF-beta-dependent EMT by stimulating activation of latent TGF-beta1. To determine whether HIF-1alpha contributes to EMT in the liver during the development of fibrosis, control and HIF-1alpha-deficient mice were subjected to BDL. FSP-1 was increased to a greater extent in the livers of control mice when compared with HIF-1alpha-deficient mice.
Results from these studies demonstrate that hypoxia stimulates hepatocyte EMT by a HIF and TGF-beta-dependent mechanism. Furthermore, these studies suggest that HIF-1alpha is important for EMT in the liver during the development of fibrosis.
背景/目的：在肝纤维化的发展过程中，肌成纤维细胞的一个重要来源是肝细胞，它通过上皮间质转化（EMT）分化为肌成纤维细胞。在上皮肿瘤和肾纤维化中，缺氧通过激活缺氧诱导因子（HIFs）是 EMT 的一个重要刺激因素。我们最近的研究表明，HIF-1α 对于肝纤维化的发展很重要。因此，我们假设缺氧通过 HIF 依赖性机制刺激肝细胞 EMT。
将原代小鼠肝细胞暴露于常氧或 1%氧气中，并评估 EMT。此外，在对照和 HIF-1α 缺陷型小鼠中进行胆管结扎（BDL），并量化 EMT。
肝细胞暴露于 1%氧气中增加了α-平滑肌肌动蛋白、波形蛋白、Snail 和成纤维细胞特异性蛋白-1（FSP-1）的表达。E-钙黏蛋白和紧密连接蛋白-1 的水平降低。HIF-1β 缺陷型肝细胞和用转化生长因子-β（TGF-β）受体抑制剂 SB431542 预处理完全阻止了缺氧对 FSP-1 和 Snail 的上调。HIF 通过刺激潜伏 TGF-β1 的激活促进 TGF-β 依赖性 EMT。为了确定 HIF-1α 是否有助于纤维化发展过程中肝脏 EMT，对对照和 HIF-1α 缺陷型小鼠进行 BDL。与 HIF-1α 缺陷型小鼠相比，对照小鼠肝脏中 FSP-1 的增加更为明显。
这些研究的结果表明，缺氧通过 HIF 和 TGF-β 依赖性机制刺激肝细胞 EMT。此外，这些研究表明，HIF-1α 对于纤维化发展过程中肝脏 EMT 很重要。
