KLF15 Cistromes Reveal a Hepatocyte Pathway Governing Plasma Corticosteroid Transport and Systemic Inflammation

Circulating corticosteroids orchestrate stress adaptation, including inhibition of inflammation. While pathways governing corticosteroid biosynthesis and intracellular signaling are understood, less is known about mechanisms controlling plasma corticosteroid transport. Here, we show hepatocyte KLF15 (Kruppel-like factor 15) controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of Serpina6, which encodes corticosteroid binding globulin (CBG). Klf15-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 Klf153xFLAG mice. Unexpectedly, liver KLF15 is predominantly promoter-enriched, including Serpina6, where it binds a palindromic GC-rich motif, opens chromatin, and transactivates genes with minimal associated gene repression. Overall, we provide new mechanistic insight into KLF15 function and identify a hepatocyte-intrinsic transcriptional module that potently regulates systemic corticosteroid transport and inflammation. Overall design: ChIP-seq (n=2) was used to define KLF15 binding map while RNA-seq (control vs KLF15-LKO, n=4) was used for gene expression and ATAC-seq (control vs KLF15-LKO, n=2) for open chromatin profiling.