Department of Pharmacology, Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ, USA.
J Lipid Res. 2023 Aug;64(8):100411. doi: 10.1016/j.jlr.2023.100411. Epub 2023 Jul 10.
The transcription factor SREBP2 is the main regulator of cholesterol homeostasis and is central to the mechanism of action of lipid-lowering drugs, such as statins, which are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic disease. Recently, SREBP2 has been implicated in leukocyte innate and adaptive immune responses by upregulation of cholesterol flux or direct transcriptional activation of pro-inflammatory genes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and crucial to the pathogenesis of cardiovascular disease. Loss of SREBF2 inhibits the production of pro-inflammatory chemokines but amplifies type I interferon response genes in response to inflammatory stimulus. Furthermore, SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing of endogenous SREBP2 reveals that SREBP2 bound to the promoter regions of two nonclassical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. SREBP2 upregulation of KLF6 was responsible for the downstream amplification of chemokine expression, highlighting a novel relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.
转录因子 SREBP2 是胆固醇稳态的主要调节剂，也是降脂药物（如他汀类药物）作用机制的核心，这些药物负责降低动脉粥样硬化患者心血管风险和死亡率的总体水平。最近，SREBP2 通过上调胆固醇通量或直接转录激活促炎基因，参与白细胞先天和适应性免疫反应。在这里，我们研究了 SREBP2 在血管内皮细胞（ECs）中的作用，因为 ECs 位于循环脂质与组织的交界处，对心血管疾病的发病机制至关重要。SREBF2 的缺失抑制了促炎趋化因子的产生，但在炎症刺激下增强了 I 型干扰素反应基因。此外，SREBP2 通过增强内源性胆固醇合成或脂蛋白摄取来调节趋化因子的表达，而是部分通过直接转录激活来调节。内源性 SREBP2 的染色质免疫沉淀测序表明，SREBP2 结合到两个参与免疫调节的非经典固醇反应基因的启动子区域，BHLHE40 和 KLF6。SREBP2 上调 KLF6 负责下游趋化因子表达的放大，突出了 ECs 中胆固醇稳态和炎症表型之间的新关系。
