Lithocholic acid can carry out in vivo functions of vitamin D

Abstract

The physiological ligand for the vitamin D receptor (VDR) is 1,25-dihydroxyvitamin D(3). Lithocholic acid (LCA), a bile acid implicated in the progression of colon cancer, was recently shown to bind to VDR with low affinity and increase expression of the xenobiotic enzymes of the CYP3A family. Thus, LCA can induce its own catabolism through the VDR. We have now found that LCA can substitute for vitamin D in the elevation of serum calcium in vitamin D-deficient rats. Further, LCA in the diet will also replace vitamin D in the mobilization of calcium from bone. Further, LCA induces CYP24-hydroxylase mRNA gene expression in the kidney of vitamin D-deficient rats. It is clear, therefore, that LCA can be absorbed into the circulation to bind to the VDR at extra-intestinal sites. These findings lend support for the idea that the VDR may have evolved from an original role in detoxification.

Fig. 1.

Serum calcium response of vitamin D-deficient rats to LCA. (A) Comparison between vitamin D-deficient (n = 10) and vitamin D-sufficient F344 rats (n = 7) fed a 0.47% calcium-purified diet with or without 4 g/kg LCA for 2 weeks. The data are expressed as mean ± SEM. Significantly different from vehicle-treated rats, ∗∗, P < 0.001. (B) Serum calcium response of vitamin-D deficient male rats on the 0.47% vitamin D-deficient diet given no LCA (n = 11), 0.1 g/kg (n = 9), 0.2 g/kg (n = 8), 0.4 g/kg (n = 11), 1 g/kg (n = 3), 2 g/kg (n = 3), or 4 g/kg (n = 3) LCA for 2 weeks. The values represent the mean ± SEM. The differences between vehicle and LCA-treated rats were significant at ∗, P < 0.05 or ∗∗∗, P < 0.01.

Fig. 2.

The effect of LCA on the mRNA levels of intestinal calcium absorption-associated genes. Male vitamin D-deficient rats were fed the 0.47% calcium-purified diet providing 0.4, 1, 2, or 4 g/kg LCA per day (n = 3) for 2 weeks. Quantitative PCR was performed on RNA from duodenal mucosa. (A) TRPV6 mRNA. (B) Calbindin D_9k mRNA. (C) ATPase mRNA. The difference between vehicle and the treatment groups was significant at ∗, P < 0.05; ∗∗, P < 0.01.

Fig. 3.

The effect of LCA on CYP24 (24-hydroxylase) mRNA in the duodenum and kidney of vitamin D-deficient and vitamin D-sufficient rats. (A) Duodenum (n = 8–11). (B) Kidney (n = 8–11). The difference between vehicle and the treatment groups was significant at ∗∗∗, P < 0.001.

Fig. 4.

LCA induces bone calcium mobilization in vivo. Serum calcium response of vitamin D-deficient rats on a 0.02% calcium diet given either 4 g/kg BW LCA or 175 ng per day of 1,25-(OH)₂D₃. Each group contained at least four animals, and the values represent the mean ± SEM. The difference between the vehicle and LCA was significant at ∗, P < 0.05 and ∗∗, P < 0.01.