Circadian control of bile acid synthesis by a KLF15-Fgf15 axis.
Shuxin Han, Sean 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, Mukesh K Jain
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.
