Editors' ChoiceMetabolism

Preventing Vitamin Overdoses?

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Sci. Signal.  11 May 2010:
Vol. 3, Issue 121, pp. ec139
DOI: 10.1126/scisignal.3121ec139

Bile acids, which are synthesized in the liver, make it possible to absorb the lipid-soluble vitamins A and D from food in the intestine. Metabolites of vitamin A activate retinoid acid receptor, such as the retinoid X receptor (RXR), whereas vitamin D binds to the vitamin D receptor (VDR). A key negative feedback loop that suppresses bile acid synthesis occurs with the binding of bile acids to the farnesoid X receptor (FXR) in the intestine, which induces expression of Fgf15 (fibroblast growth factor 15). Secreted Fgf15 represses the hepatic expression of Cyp7a1, which encodes a rate-limiting enzyme in bile acid synthesis, a transcriptional regulatory event that requires the nuclear receptor SHP (small heterodimer partner). Schmidt et al. found that vitamins A and D decreased bile acid synthesis. VDR–/– mice had larger bile acid pools than wild-type mice, as well as increased abundance of Cyp7a1 and decreased abundance of Fgf15. In wild-type mice, vitamin D treatment (in the form of 1α,25-dihydroxyvitamin D3) decreased the abundance of Cyp7a1 and increased that of Fgf15; vitamin D did not decrease the abundance of Cyp7a1 in Fgf15–/– or FXR–/– mice. Chromatin immunoprecipitation analysis identified a VDR response element in the promoter region of Fgf15. In wild-type mice, vitamin A treatment (in the form of retinyl palmitate) increased Fgf15 and Shp abundance and decreased Cyp7a1 abundance in an RXR-dependent manner. In FXR–/– mice, vitamin A did not increase the abundance of Fgf15 (suggesting a requirement for a RXR-FXR heterodimer) but still decreased the abundance of Cyp7a1 in a SHP-dependent manner (suggesting that RXR can also act independently of FXR). Treatment of wild-type mice with cholestyramine, a bile acid–binding resin that decreases bile acid absorption and results in increased bile acid synthesis, reduced the abundance of Fgf15 and Shp and increased that of Cyp7a1. These effects were rescued by treatment of vitamin A but not vitamin D. The authors propose that vitamin A analogs could be used to treat bile acid malabsorption syndrome, which is characterized by defective feedback repression of bile acid synthesis.

D. R. Schmidt, S. R. Holmstrom, K. Fon Tacer, A. L. Bookout, S. A. Kliewer, D. J. Mangelsdorf, Regulation of bile acid synthesis by fat-soluble vitamins A and D. J. Biol. Chem. 285, 14486–14494 (2010). [Abstract] [Full Text]

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