Abstract
Vitamin D receptor (VDR), a nuclear receptor that regulates calcium homeostasis, has been found to function as a receptor for secondary bile acids. Because the in vivo role of VDR in bile acid metabolism remains unknown, we investigated the effect of VDR activation in a mouse model of cholestasis. We treated mice with 1α-hydroxyvitamin D3 [1α(OH)D3] after bile duct ligation (BDL) and examined mRNA expression and cytokine levels. 1α(OH)D3 treatment altered the expression of genes involved in bile acid synthesis and transport in the liver, kidney, and intestine but did not decrease bile acid levels in the plasma and liver of BDL mice. 1α(OH)D3 treatment suppressed mRNA expression of proinflammatory cytokines in the liver and strongly decreased the plasma levels of proinflammatory cytokines in BDL mice. These findings indicate that 1α(OH)D3 regulates a network of bile acid metabolic genes and represses proinflammatory cytokine expression in BDL mice. VDR ligands have the potential to prevent the cholestasis-induced inflammatory response.
Footnotes
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This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology, Japan; the Ministry of Health, Labor, and Welfare, Japan; and Nihon University [Nihon University Joint Research Grant for 2007].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.145987.
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ABBREVIATIONS: FXR, farnesoid X receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; VDR, vitamin D receptor; 1,25(OH)2D3, 1α,25-dihydroxyvitamin D3; TNF, tumor necrosis factor; BDL, bile duct ligation; Cyp8b1, sterol 12α-hydroxylase; Bsep, bile salt export pump; Oatp, organic anion-transporting polypeptide; Mrp, multidrug resistance-associated protein; 1α(OH)D3, 1α-hydroxyvitamin D3; Cyp24a1, 25-hydroxyvitamin D 24-hydroxylase; Trpv, transient receptor potential vanilloid; Cyp27b1, 25-hydroxyvitamin D 1α-hydroxylase; Cyp7a1, cholesterol 7α-hydroxylase; Shp, short heterodimer partner; Ntcp, sodium taurocholate-cotransporting polypeptide; Ost, organic solute transporter; ALT, alanine aminotransferase; IL, interleukin; IFN, interferon.
- Received September 10, 2008.
- Accepted November 5, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Vitamin D3 Modulates the Expression of Bile Acid Regulatory Genes and Represses Inflammation in Bile Duct-Ligated Mice
