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

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, Xudong Liao, Jonathan A. Epstein and Mukesh K. Jain ()
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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
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
Mukesh K. Jain: Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8231

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