Abstract
Cholic acid (CA) feeding of farnesoid X receptor (Fxr)-null mice results in markedly elevated hepatic bile acid levels and liver injury. In contrast, Fxr-null mice fed cholesterol plus CA (CA+Chol) do not exhibit liver injury, and hepatic bile acid levels and bile acid pool size are reduced 51 and 40%, respectively, compared with CA-treated Fxr-null mice. These decreases were not observed in wild-type mice. Despite a reduced bile acid pool size, hepatic Cyp7a1 mRNA expression was increased in Fxr-null mice fed the CA+Chol diet, and biliary bile acid output was not changed. Analysis of other potential protective mechanisms revealed significant decreases in portal blood bile acid concentrations and a reduced ileal bile acid absorption capacity, as estimated using an in situ loop method. Fecal bile acid excretion was also increased in Fxr-null mice fed the CA+Chol versus CA diet. The decreased ileal bile acid absorption correlated with decreased ileal apical sodium-dependent bile salt transporter (ASBT) protein expression in brush-border membranes. These results suggest a critical role for ileal bile acid absorption in regulation of hepatic bile acid levels in Fxr-null mice fed CA+Chol. Furthermore, experiments with Fxr-null mice suggest that cholesterol feeding can down-regulate ASBT expression through a pathway independent of FXR.
Footnotes
-
This study was supported by the Ministry of Education, Science and Culture, Japan [Grants 17390039, 17590114]; the Ministry of Health, Labor and Welfare, Japan [Grant H17-toxico-ippan-001]; and the National Institutes of Health [Grant DK-47987].
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.022590.
-
ABBREVIATIONS: Chol, cholesterol; FXR, farnesoid X receptor; ASBT, apical sodium-dependent bile salt transporter; OSTα, organic solute transporter α; FGF, fibroblast growth factor; CA, cholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; DCA, deoxycholic acid; TDCA, taurodeoxycholic acid; HPLC, high-performance liquid chromatography; ALT, alanine aminotransferase; ALP, alkaline phosphatase; BBM, brush-border membrane; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LXR, liver X receptor; PXR, pregnane X receptor.
- Received May 29, 2008.
- Accepted November 3, 2008.
- U.S. Government work not protected by U.S. copyright.
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|