Attenuated Accumulation of Novel Fluorine (19F)-Labeled Bile Acid Analogues in Gallbladders of Fibroblast Growth Factor-15 (FGF15)-Deficient Mice

摘要

Our work has focused on defining the utility of fluorine (¹⁹F)-labeled bile acid analogues and magnetic resonance imaging (MRI) to identify altered bile acid transport in vivo. In the current study, we explored the ability of this approach to differentiate fibroblast growth factor-15 (FGF15)- deficient from wild-type (WT) mice, a potential diagnostic test for bile acid diarrhea, a commonly misdiagnosed disorder. FGF15 is the murine homologue of human FGF19, an intestinal hormone whose deficiency is an underappreciated cause of bile acid diarrhea. In a pilot and three subsequent pharmacokinetic studies, we treated mice with two ¹⁹F-labeled bile acid analogues, CA-lys-TFA and CA-sar-TFMA. After oral dosing, we quantified ⁹F-labeled bile acid analogue levels in the gallbladder, liver, small and large intestine, and plasma using liquid chromatography mass spectrometry (LC-MS/MS). Both ¹⁹F bile acid analogues concentrated in the gallbladders of FGF15-deficient and WT mice, attaining peak concentrations at approximately 8.5 h after oral dosing. However, analogue levels in gallbladders of FGF15-deficient mice were several-fold less compared to those in WT mice. Live-animal ¹⁹F MRI provided agreement with our LC-MS/MS-based measures; we detected robust CA-lys-TFA ¹⁹F signals in gallbladders of WT mice but no signals in FGF15-deficient mice. Our finding that ¹⁹F MRI differentiates FGF15-deficient from WT mice provides additional proof-of-concept for the development of ¹⁹F bile acid analogues and ¹⁹F MRI as a clinical test to diagnose bile acid diarrhea due to FGF19 deficiency and other disorders.