Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, Germany.
Int J Biochem Cell Biol. 2010 Feb;42(2):241-52. doi: 10.1016/j.biocel.2009.10.002. Epub 2009 Oct 12.
ATP-binding cassette transporter A1 plays (ABCA1) a major role in reverse cholesterol transport, a process closely related to atherogenesis. In the thickening atherosclerotic lesions lipid loaded macrophages are exposed to regions of local hypoxia that may influence reverse cholesterol transport. Here we studied the effect of hypoxia on ABCA1 regulation and cholesterol efflux in human macrophages. We found that the hypoxia-inducible factor 1 (HIF-1) specifically binds to the HIF-1 response element of the ABCA1 promoter and the HIF-1 complex increases ABCA1 promoter activity along with ABCA1 expression. Primary human macrophages exposed to hypoxia or expressing constitutively active HIF-1alpha responded with a potent change in ABCA1 expression, which showed a strong correlation with HIF-1beta expression (r: 0.95-0.91). Moreover, ABCA1-mediated cholesterol efflux was also found to be regulated by HIF-1beta under hypoxia. In vivo, in macrophages prepared from human atherosclerotic lesions ABCA1 levels showed a strong correlation with HIF-1beta expression. This in vivo regulatory mechanism was confirmed in human pre-eclamptic placentas, a clinical condition with severe local hypoxia. These results demonstrate that HIF-1beta availability determines ABCA1 expression and cholesterol efflux in macrophages under hypoxia and may contribute to the interpersonal variability of atherosclerotic lesion progression.
三磷酸腺苷结合盒转运体 A1（ABCA1）在胆固醇逆向转运中起着重要作用，而胆固醇逆向转运与动脉粥样硬化的发生密切相关。在动脉粥样硬化病变的增厚部位，载脂蛋白的巨噬细胞暴露于局部缺氧区域，这可能会影响胆固醇的逆向转运。在这里，我们研究了缺氧对人巨噬细胞中 ABCA1 调节和胆固醇外排的影响。我们发现缺氧诱导因子 1（HIF-1）特异性结合 ABCA1 启动子的 HIF-1 反应元件，HIF-1 复合物增加 ABCA1 启动子活性和 ABCA1 表达。原发性人巨噬细胞暴露于缺氧或表达组成型激活的 HIF-1α，ABCA1 表达发生强烈变化，这与 HIF-1β表达呈强相关性（r：0.95-0.91）。此外，还发现 ABCA1 介导的胆固醇外排也受缺氧下 HIF-1β的调节。在体内，从人动脉粥样硬化病变中分离出的巨噬细胞中 ABCA1 水平与 HIF-1β表达呈强相关性。这种体内调节机制在人先兆子痫胎盘得到了证实，这是一种局部严重缺氧的临床情况。这些结果表明，HIF-1β的可用性决定了巨噬细胞在缺氧下的 ABCA1 表达和胆固醇外排，并可能导致动脉粥样硬化病变进展的个体间变异性。
