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.
Highlights
Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism
Studies over the past decade have revealed that feedback inhibition of bile acids (BAs) synthesis involves ileal farnesoid X receptor (FXR/NR1H4)-induced fibroblast growth factor 15 (Fgf15)[9] and hepatic FXR-induced atypical nuclear receptor small heterodimer partner (Shp/Nr0b2)[10]
FGF15 is subsequently secreted into the circulation where it is transported to the liver and binds its cognate receptor fibroblast growth factor receptor 4/FGFR4 and co-receptor bKlotho on hepatocytes[13] and activates a signalling pathway that culminates in repression of Cyp7a1
Summary
Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism. 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 Fgf[15] expression. Elucidation of this novel pathway controlling circadian BA production has important implications for physiologic control of nutrient availability and metabolic homeostasis. Studies over the past decade have revealed that feedback inhibition of BA synthesis involves ileal farnesoid X receptor (FXR/NR1H4)-induced fibroblast growth factor 15 (Fgf15)[9] and hepatic FXR-induced atypical nuclear receptor small heterodimer partner (Shp/Nr0b2)[10] These studies indicate that expression of Fgf[15], which occurs principally in enterocytes of the ileum[11,12], is induced by BA-mediated activation of the nuclear receptor FXR in enterocytes. Several recent reports have documented that Fgf15/19 levels exhibit diurnal variation[14,15], the molecular basis and functional importance in regulating circadian BA production is unknown
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