Regulation of bile acid synthesis by fat-soluble vitamins A and D.
Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15, an intestine-derived hormone that acts on liver to inhibit Cyp7a1. These effects were mediated through distinct cis-acting response elements in the promoter and intron of Fgf15. Interestingly, transactivation of both response elements appears to be required to maintain basal Fgf15 expression levels in vivo. Furthermore, whereas induction of Fgf15 by vitamin D is mediated through its receptor, the induction of Fgf15 by vitamin A is mediated through the retinoid X receptor/farnesoid X receptor heterodimer and is independent of bile acids, suggesting that this heterodimer functions as a distinct dietary vitamin A sensor. Notably, vitamin A treatment reversed the effects of the bile acid sequestrant cholestyramine on Fgf15, Shp, and Cyp7a1 expression, suggesting a potential therapeutic benefit of vitamin A under conditions of bile acid malabsorption. These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption.
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.
Daniel R
DR
Schmidt
Sam R
SR
Holmstrom
Klementina
K
Fon Tacer
Angie L
AL
Bookout
Steven A
SA
Kliewer
David J
DJ
Mangelsdorf
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015153:Blotting, Western; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology; D018167:Receptors, Calcitriol / Q000502:physiology; D047488:Retinoid X Receptors / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014801:Vitamin A / Q000378:metabolism*; D014807:Vitamin D / Q000378:metabolism*
D001647:Bile Acids and Salts; C496283:Fxr1h protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; C108526:fibroblast growth factor 15, mouse; D014801:Vitamin A; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse