title: Circadian control of bile acid synthesis by a KLF15-Fgf15 axis.
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.
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Shuxin
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Sean Shuxin
authors.initials: SS
authors.lastname: Han
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.affiliation: 1] Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Lilei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Panjamaporn
authors.initials: P
authors.lastname: Sangwung
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Derin
authors.initials: D
authors.lastname: Tugal
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: G Brandon
authors.initials: GB
authors.lastname: Atkins
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.affiliation: Mouse Metabolic Phenotype Center, Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tso
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.affiliation: 1] Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D015153:Blotting, Western; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D014157:Transcription Factors; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4