TY - JOUR
T1 - Circadian control of bile acid synthesis by a KLF15-Fgf15 axis
AU - Han, Sean
AU - Zhang, Rongli
AU - Jain, Rajan
AU - Shi, Hong
AU - Zhang, Lilei
AU - Zhou, Guangjin
AU - Sangwung, Panjamaporn
AU - Tugal, Derin
AU - Atkins, G. Brandon
AU - Prosdocimo, Domenick A.
AU - Lu, Yuan
AU - Han, Xiaonan
AU - Tso, Patrick
AU - Liao, Xudong
AU - Epstein, Jonathan A.
AU - Jain, Mukesh K.
N1 - Funding Information:
We thank Dr John Chiang (Northeast Ohio Medical University) for his generous donation of multiple plasmids. We also thank Dr Steven Kliewer (University of Texas Southwestern Medical Center) for generous supply of Fgf15−/− mouse plasma and critical advice. We thank Dr Dongsheng Zhang (Cincinnati Children’s Hospital Medical Center) for the technique assistance. We acknowledge the Penn CVI Histology Core for the help with ISHs. We also thank the scientific artist Robert Flewell (Madison Creative) for making the schematic diagrams. This research is supported by NIH grants T32-HL105338-03 (S.H.) and R01-HL119780 (M.J.).
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/6/4
Y1 - 2015/6/4
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms8231
DO - 10.1038/ncomms8231
M3 - Article
C2 - 26040986
AN - SCOPUS:84930655782
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 7231
ER -