Because of their unique physicochemical properties, bile acids are essential structural components of lipid micelles (11
). In this capacity, bile acids promote the intestinal absorption of lipids and lipid-soluble vitamins. Here, we have revealed an unexpected link between lipid-soluble vitamins and bile acid biosynthesis. Surprisingly, vitamins A and D exert negative feedback on bile acid synthesis in vivo
by decreasing Cyp7a1
expression. FGF15 and SHP play a central role in the feedback regulation of bile acid synthesis by bile acids and FXR (31
). Our study shows that FGF15 is integral to the mechanism of Cyp7a1
regulation by vitamin D and that both FGF15 and SHP are important for the regulation of bile acid synthesis by vitamin A.
We found that VDR transcriptionally regulated Fgf15
in the intestine and that this pathway was essential for the repression of bile acid synthesis by vitamin D. Surprisingly, VDR was required to maintain normal Fgf15
expression and bile acids levels in vivo
. Together, these results demonstrate that vitamin D and its receptor contribute to the feedback regulation of bile acid synthesis by controlling expression of the endocrine hormone FGF15. We note that VDR expression has been reported in non-parenchymal cells in the liver (32
), leaving open the possibility that paracrine signals might also contribute to VDR-dependent regulation of bile acid synthesis.
repression by vitamin D required an intact FXR signaling pathway, indicating that VDR activation alone is not sufficient to suppress bile acid synthesis. There are at least two possible explanations for this finding. First, activation of both VDR and FXR may be required to induce Fgf15
to the level required for Cyp7a1
suppression. Second, as has recently been shown for FXR (19
), feedback repression of bile acid synthesis may require corresponding signals in the intestine and liver, the latter of which does not occur upon activation of VDR alone.
Vitamin A repressed Cyp7a1 through both FXR-dependent and FXR-independent mechanisms. Ligands for RXR, but not RAR, induced Fgf15, and FXR was required for the induction of Fgf15 by vitamin A. These results indicate that induction of Fgf15 expression by vitamin A occurs through RXR as the obligate heterodimeric partner of the RXR/FXR heterodimer complex. This finding provides evidence that RXR functions as a vitamin A receptor in vivo and demonstrates that the RXR/FXR heterodimer can serve as a sensor for dietary vitamin A. In contrast to its effects on FGF15 expression, vitamin A-dependent induction of Shp expression did not require FXR. Interestingly, we found that the RAR ligand TTNPB induced Shp and suppressed Cyp7a1, suggesting that Shp induction by RAR may be an FXR-independent mechanism whereby vitamin A suppresses Cyp7a1. Taken together, these results point to two distinct nuclear receptor-mediated mechanisms by which vitamin A regulates bile acid synthesis.
Under normal physiological conditions, bile acids are efficiently reabsorbed in the ileum (11
). Bile acid malabsorption is a pathological condition often seen in patients with Crohn disease or ileal resection and is characterized by reduced ileal bile acid reabsorption and delivery of large quantities of bile acids to the colon (30
). Increased luminal concentrations of bile acids in the colon induce fluid secretion, resulting in cholerheic enteropathy and the characteristic symptom of watery diarrhea. Bile acid sequestrants are currently the primary therapy and provide symptomatic relief but do not correct bile acid overproduction and hypersecretion by the liver. The exciting finding that vitamin A induces Fgf15
and suppresses bile acid synthesis under conditions of interrupted bile acid reabsorption suggests that vitamin A analogs may provide therapeutic benefit to patients with bile acid malabsorption and increased hepatic bile acid synthesis. Interestingly, a subset of patients with bile acid malabsorption have increased hepatic bile acid synthesis despite normal ileal bile acid transport. This condition, termed idiopathic bile acid malabsorption, has recently been shown to be associated with decreased plasma levels of FGF19 (33
). It is not known why FGF19 levels are abnormally low in these patients. Our data suggest that vitamins A and D may be useful tools to examine the underlying cause of low FGF19 levels in these patients.
Elevated levels of bile acid in the colon may promote colon cancer, whereas vitamin D is associated with reduced risk of colon cancer (34
). We showed previously that VDR is activated by lithocholic acid and induces enzymes that detoxify bile acids in the colon (22
). The present study suggests that vitamin D-dependent regulation of bile acid synthesis may be an additional mechanism by which vitamin D protects against the tumor-promoting effects of toxic bile acids.
With regard to the mechanism underlying the hormonal effects of vitamin D, an interesting parallel emerges between the regulation of bile acid synthesis by FGF15 and the role of FGF23 in renal phosphate metabolism. Previous studies have shown that vitamin D induces Fgf23
in bone and that FGF23 signals in a bone-kidney axis to control phosphate absorption and vitamin D metabolism in the kidney (38
). In this study, we have shown that vitamin D induces Fgf15
in the intestine, which signals in an intestine-liver axis to regulate bile acid synthesis in the liver. Thus, a paradigm emerges in which endocrine fibroblast growth factors function as downstream messengers to mediate the homeostatic effects of vitamin D and coordinate vitamin D signaling between organ systems.
In summary, our findings highlight the importance of nuclear receptors in the regulation of bile acid metabolism and provide mechanistic insight into the elegant signaling pathways involving FGF15 and SHP that govern feedback repression of bile acid biosynthesis. We speculate that the mechanisms allowing vitamins A and D to control feedback repression of bile acid synthesis may have evolved to protect the organism from exposure to potentially toxic levels of lipid-soluble vitamins in the diet.