College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Arterioscler Thromb Vasc Biol. 2011 Dec;31(12):2949-56. doi: 10.1161/ATVBAHA.111.235788. Epub 2011 Sep 22.
Atherosclerosis is a chronic and progressive inflammatory disease of the arteries that is characterized by subendothelial accumulation of lipid-rich macrophages, called foam cells. We sought to identify the molecular details of cross-talk between liver X receptor α (LXRα) and hypoxia-inducible factor 1α (HIF-1α) for the formation of triglyceride-rich foam cells under hypoxic conditions.
We first observed that expression of LXRα and its target lipogenic genes was time-dependently induced in human primary macrophages and RAW 264.7 cells under hypoxia. Similarly, TO901317, an activator of LXRα, enhanced the expression level and the transcriptional activity of HIF-1α. Second, we demonstrated that LXRα increased HIF-1α protein stability through a physical interaction between the ligand binding domain of LXRα and the oxygen-dependent degradation domain of HIF-1α. Third, we found that the activation of HIF-1α or LXRα synergistically induced triglyceride accumulation in macrophages. Finally, we showed that LXRα and HIF-1α were codistributed in the macrophages of atherosclerotic lesions of patients.
These results suggest that the positive feed-forward regulation of transcriptional activity and protein stability of LXRα and HIF-1α has an important impact in foam cell formation.
动脉粥样硬化是一种慢性进行性的动脉炎症疾病，其特征是富含脂质的巨噬细胞（泡沫细胞）在下皮细胞下积聚。我们试图确定 LXRα（肝 X 受体 α）与 HIF-1α（缺氧诱导因子 1α）之间的分子细节，以了解在缺氧条件下形成富含甘油三酯的泡沫细胞的过程。
我们首先观察到，在缺氧条件下，人原代巨噬细胞和 RAW 264.7 细胞中 LXRα及其靶基因的脂生成基因表达随时间呈时间依赖性诱导。同样，LXRα 的激动剂 TO901317 增强了 HIF-1α 的表达水平和转录活性。其次，我们证明 LXRα 通过 LXRα 的配体结合域与 HIF-1α 的氧依赖性降解域之间的物理相互作用增加了 HIF-1α 蛋白的稳定性。第三，我们发现 HIF-1α 或 LXRα 的激活协同诱导巨噬细胞中甘油三酯的积累。最后，我们表明 LXRα 和 HIF-1α 在动脉粥样硬化病变患者的巨噬细胞中分布。
这些结果表明，LXRα 和 HIF-1α 的转录活性和蛋白稳定性的正反馈调节对泡沫细胞的形成有重要影响。
