University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, Neulaniementie 2, FIN-70211 Kuopio, Finland.
Atherosclerosis. 2012 Dec;225(2):335-40. doi: 10.1016/j.atherosclerosis.2012.09.039. Epub 2012 Oct 9.
Endothelial lipase (EL) regulates HDL cholesterol levels and in inflammatory states, like atherosclerosis, EL expression is increased contributing to low HDL cholesterol. The regulation of EL expression is poorly understood and has mainly been attributed to inflammatory stimuli. As sterol regulatory element binding proteins (SREBPs) are regulators of genes involved in lipid metabolism, we hypothesized that EL is regulated by SREBPs and that EL expression is modified by the SREBP activator vascular endothelial growth factor A (VEGF-A).
and results: Quantitative PCR and Western blot results demonstrated that starvation increased EL expression in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). Also, 25-hydroxycholesterol (25HC), an inhibitor of SREBP activation inhibited EL expression. With siRNA-mediated inhibition of SREBPs the effect of starvation was shown to be SREBP-2 dependent. VEGF-A decreased EL expression in both endothelial cell lines used, most likely via inhibition of SREBP-2 binding determined by chromatin immunoprecipitation (ChIP). Furthermore, in atherosclerosis prone LDLR(-/-)ApoB(100/100) mice, systemic adenoviral gene transfer with human VEGF-A decreased EL mRNA in peripheral tissues and increased plasma HDL cholesterol.
These results identify SREBPs as novel regulators of EL expression. VEGF-A as an endogenous EL inhibitor could be therapeutically relevant in atherosclerosis by increasing systemic HDL cholesterol levels.
内皮脂肪酶（EL）调节高密度脂蛋白胆固醇水平，在炎症状态下，如动脉粥样硬化，EL 表达增加，导致高密度脂蛋白胆固醇降低。EL 表达的调节机制尚不清楚，主要归因于炎症刺激。由于固醇调节元件结合蛋白（SREBPs）是参与脂质代谢的基因的调节剂，我们假设 EL 受 SREBPs 调节，并且 EL 表达受 SREBP 激活剂血管内皮生长因子 A（VEGF-A）修饰。
定量 PCR 和 Western blot 结果表明，饥饿增加了人脐静脉内皮细胞（HUVECs）和人主动脉内皮细胞（HAECs）中的 EL 表达。此外，SREBP 激活抑制剂 25-羟胆固醇（25HC）抑制 EL 表达。用 SREBP 特异性 siRNA 抑制，表明饥饿的作用是依赖于 SREBP-2 的。VEGF-A 降低了两种内皮细胞系中 EL 的表达，这很可能是通过染色质免疫沉淀（ChIP）测定抑制 SREBP-2 结合来实现的。此外，在动脉粥样硬化易感 LDLR(-/-)ApoB(100/100) 小鼠中，全身性腺病毒基因转移用人类 VEGF-A 降低了外周组织中的 EL mRNA，并增加了血浆高密度脂蛋白胆固醇。
这些结果确定了 SREBPs 作为 EL 表达的新调节剂。作为内源性 EL 抑制剂的 VEGF-A 通过增加全身 HDL 胆固醇水平，在动脉粥样硬化中可能具有治疗相关性。
