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

Sean 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; Mukesh K. Jain

doi:10.1038/ncomms8231

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

Sean 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, Mukesh K. Jain

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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.

Original language	English (US)
Article number	7231
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8231
State	Published - Jun 4 2015
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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.",

author = "Sean Han and Rongli Zhang and Rajan Jain and Hong Shi and Lilei Zhang and Guangjin Zhou and Panjamaporn Sangwung and Derin Tugal and Atkins, {G. Brandon} and Prosdocimo, {Domenick A.} and Yuan Lu and Xiaonan Han and Patrick Tso and Xudong Liao and Epstein, {Jonathan A.} and Jain, {Mukesh K.}",

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doi = "10.1038/ncomms8231",

language = "English (US)",

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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.

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

Abstract

ASJC Scopus subject areas

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