Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
Cell Metab. 2011 May 4;13(5):540-9. doi: 10.1016/j.cmet.2011.04.001.
We show that mice with a targeted deficiency in the gene encoding the lipogenic transcription factor SREBP-1a are resistant to endotoxic shock and systemic inflammatory response syndrome induced by cecal ligation and puncture (CLP). When macrophages from the mutant mice were challenged with bacterial lipopolysaccharide, they failed to activate lipogenesis as well as two hallmark inflammasome functions, activation of caspase-1 and secretion of IL-1β. We show that SREBP-1a activates not only genes required for lipogenesis in macrophages but also the gene encoding Nlrp1a, which is a core inflammasome component. Thus, SREBP-1a links lipid metabolism to the innate immune response, which supports our hypothesis that SREBPs evolved to regulate cellular reactions to external challenges that range from nutrient limitation and hypoxia to toxins and pathogens.
我们发现，靶向敲除编码脂肪生成转录因子 SREBP-1a 的基因的小鼠对盲肠结扎和穿刺（CLP）诱导的内毒素休克和全身炎症反应综合征具有抗性。当来自突变小鼠的巨噬细胞受到细菌脂多糖的刺激时，它们既不能激活脂肪生成，也不能激活两个标志性的炎症小体功能，即半胱氨酸天冬氨酸蛋白酶-1 的激活和白细胞介素-1β 的分泌。我们发现，SREBP-1a 不仅激活了巨噬细胞中脂肪生成所需的基因，还激活了编码 Nlrp1a 的基因，Nlrp1a 是炎症小体的核心成分。因此，SREBP-1a 将脂质代谢与先天免疫反应联系起来，这支持了我们的假设，即 SREBPs 的进化是为了调节细胞对从营养限制和缺氧到毒素和病原体等各种外部挑战的反应。
