4.8 Article

KLF15 cistromes reveal a hepatocyte pathway governing plasma corticosteroid transport and systemic inflammation

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SCIENCE ADVANCES
卷 8, 期 10, 页码 -

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AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abj2917

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资金

  1. NIH [R01 DK060540, R01 DK106404, P30 DK098722, R01 HL146654, K01 DK121875, R56 HL158531]
  2. CPRIT Scholar for Cancer Research
  3. CPRIT [RR150093]
  4. Swiss National Science Foundation [P400PM_186704]
  5. American Heart Association [17PRE33670181]
  6. UCSF Moritz-Heyman Discovery Fellowship
  7. TRDRP Fellowship [T30DT1006]
  8. Cincinnati Children's Research Foundation
  9. HI Translational Grant
  10. Swiss National Science Foundation (SNF) [P400PM_186704] Funding Source: Swiss National Science Foundation (SNF)

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This study reveals that hepatocyte KLF15 controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of Serpina6. Moreover, KLF15 is predominantly enriched in the promoter regions of liver cells, regulating gene transcription activity through binding specific DNA sequences, with minimal associated gene repression.
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 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 Klf15(3xFLAG) 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 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.

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