Jiang Zhen, Elsarrag Selma Z, Duan Qiming, LaGory Edward L, Wang Zhe, Alexanian Michael, McMahon Sarah, Rulifson Ingrid C, Winchester Sarah, Wang Yi, Vaisse Christian, Brown Jonathan D, Quattrocelli Mattia, Lin Charles Y, Haldar Saptarsi M
Amgen Research, South San Francisco, CA 94080, USA.
Gladstone Institutes, San Francisco, CA 94158, USA.
Sci Adv. 2022 Mar 11;8(10):eabj2917. doi: 10.1126/sciadv.abj2917. Epub 2022 Mar 9.
Circulating corticosteroids orchestrate stress adaptation, including inhibition of inflammation. While pathways governing corticosteroid biosynthesis and intracellular signaling are well understood, less is known about mechanisms controlling plasma corticosteroid transport. Here, we show that hepatocyte KLF15 (Kruppel-like factor 15) controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of , which encodes corticosteroid-binding globulin (CBG). -deficient mice have profoundly low CBG, reduced plasma corticosteroid binding capacity, and heightened mortality during inflammatory stress. These defects are completely rescued by reconstituting CBG, supporting that KLF15 works primarily through CBG to control plasma corticosterone homeostasis. To understand transcriptional mechanisms, we generated the first KLF15 cistromes using newly engineered mice. Unexpectedly, liver KLF15 is predominantly promoter enriched, including , where it binds a palindromic GC-rich motif, opens chromatin, and transactivates genes with minimal associated direct gene repression. Overall, we provide critical mechanistic insight into KLF15 function and identify a hepatocyte-intrinsic transcriptional module that potently regulates systemic corticosteroid transport and inflammation.
循环中的皮质类固醇协调应激适应，包括抑制炎症。虽然控制皮质类固醇生物合成和细胞内信号传导的途径已为人熟知，但对控制血浆皮质类固醇转运的机制了解较少。在这里，我们表明肝细胞KLF15（Kruppel样因子15）通过直接转录激活编码皮质类固醇结合球蛋白（CBG）的基因来控制血浆皮质类固醇转运和炎症反应。CBG缺陷小鼠的CBG水平极低，血浆皮质类固醇结合能力降低，在炎症应激期间死亡率升高。通过重建CBG可完全挽救这些缺陷，支持KLF15主要通过CBG来控制血浆皮质酮稳态。为了了解转录机制，我们使用新工程化的小鼠生成了首个KLF15顺反组。出乎意料的是，肝脏KLF15主要富集在启动子区域，包括它结合富含GC的回文基序、打开染色质并激活基因且极少伴有相关直接基因抑制的区域。总体而言，我们提供了对KLF15功能的关键机制见解，并鉴定出一个强有力调节全身皮质类固醇转运和炎症的肝细胞内源性转录模块。
