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Circadian control of bile acid synthesis by a KLF15-Fgf15 axis

Author

Listed:
  • Shuxin Han

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Rongli Zhang

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Rajan Jain

    (Perelman School of Medicine at the University of Pennsylvania
    Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania
    Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania)

  • Hong Shi

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Lilei Zhang

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Guangjin Zhou

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Panjamaporn Sangwung

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Derin Tugal

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • G. Brandon Atkins

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Domenick A. Prosdocimo

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Yuan Lu

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Xiaonan Han

    (Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center)

  • Patrick Tso

    (Mouse Metabolic Phenotype Center, Metabolic Diseases Institute and the University of Cincinnati College of Medicine)

  • Xudong Liao

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

  • Jonathan A. Epstein

    (Perelman School of Medicine at the University of Pennsylvania
    Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania
    Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania)

  • Mukesh K. Jain

    (Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center)

Abstract

Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism. Production of bile acids (BAs), which facilitate digestion and absorption of nutrients, is a major regulator of this process. Here we identify a KLF15-Fgf15 signalling axis that regulates circadian BA production. Systemic Klf15 deficiency disrupted circadian expression of key BA synthetic enzymes, tissue BA levels and triglyceride/cholesterol absorption. Studies in liver-specific Klf15-knockout mice suggested a non-hepatic basis for regulation of BA production. Ileal Fgf15 is a potent inhibitor of BA synthesis. Using a combination of biochemical, molecular and functional assays (including ileectomy and bile duct catheterization), we identify KLF15 as the first endogenous negative regulator of circadian Fgf15 expression. Elucidation of this novel pathway controlling circadian BA production has important implications for physiologic control of nutrient availability and metabolic homeostasis.

Suggested Citation

  • Shuxin Han & Rongli Zhang & Rajan Jain & Hong Shi & Lilei Zhang & Guangjin Zhou & Panjamaporn Sangwung & Derin Tugal & G. Brandon Atkins & Domenick A. Prosdocimo & Yuan Lu & Xiaonan Han & Patrick Tso , 2015. "Circadian control of bile acid synthesis by a KLF15-Fgf15 axis," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8231
    DOI: 10.1038/ncomms8231
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