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dc.contributor.advisorKlaassen, Curtis D.
dc.contributor.authorSong, Peizhen
dc.date.accessioned2011-07-04T20:24:50Z
dc.date.available2011-07-04T20:24:50Z
dc.date.issued2010-12-16
dc.date.submitted2010
dc.identifier.otherhttp://dissertations.umi.com/ku:11225
dc.identifier.urihttp://hdl.handle.net/1808/7756
dc.description.abstractThe dissertation investigates the non-hepatotoxic doses of five bile acids (BAs) in the feed of mice, as well as adaptations in the expression of genes involved in BA homeostasis and the possible roles of FXR-mediated signaling in regulating these genes. Mice were fed four main BAs, cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA), and the therapeutic BA ursodeoxycholic acid (UDCA), at various concentrations in their diets (0.01, 0.03, 0.1, 0.3, 1.0, or 3.0%), as well as the BA sequestrant cholestyramine (resin) at 2% in their diets, for one week. Subsequently, serum alanine aminotransferase (ALT), serum and hepatic BA concentrations, as well as mRNAs of genes involved in BA homeostasis were quantified. The data showed: 1) LCA produced hepatotoxicity at 0.03%, indicated by increases in serum ALT and serum BA concentration, as did DCA at 0.1%, and CDCA and CA at 0.3% in the diet. UDCA at 0.3% in the diet might be hepatotoxic because the serum BA concentration was increased but the serum ALT did not increase. 2) Feeding BAs at hepatotoxic doses altered liver BA composition. 3) The mRNA of SHP and Cyp7a1 in the liver was increased by all doses of BAs. In contrast, BA regulation of the mRNA of the hepatic Cyp8b1 and the ileal Fgf15 are BA species dependent: CA and DCA at all doses increased Fgf15 and decreased Cyp8b1, whereas, CDCA and LCA at high doses increased Fgf15 and decreased Cyp8b1 mRNA. 4) Feeding resin increased the mRNA Cyp7a1 and Cyp8b1 in the liver and Fgf15 in the ileum. In conclusion, my dissertation demonstrates the non-hepatotoxic doses of individual BAs are as follows: 0.1% or lower in the diets for CA, CDCA, and UDCA, 0.03% for DCA, and 0.01% or lower for LCA. In addition, the altered liver BA composition after non-hepatotoxic doses of BA-feeding are able to trigger the hepatic FXR-SHP and the ileal FXR-Fgf15 signaling pathways, which coordinately regulate Cyp7a1 and Cyp8b1. Moreover, the the decreased expression of the ileal Fgf15 after feeding resin caused increases in mRNA expression of CYp7a1 and Cyp8b1.
dc.format.extent186 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsThis item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
dc.subjectToxicology
dc.subjectPathology
dc.subjectBile acids
dc.subjectCholestyramine resin
dc.subjectCyp7a1
dc.subjectCyp8b1
dc.subjectFgf15
dc.subjectFxr
dc.titleEFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE
dc.typeDissertation
dc.contributor.cmtememberCopple, Bryan
dc.contributor.cmtememberGuo, Grace
dc.contributor.cmtememberHagenbuch, Bruno
dc.contributor.cmtememberStaudinger, Jeff L.
dc.thesis.degreeDisciplinePharmacology, Toxicology & Therapeutics
dc.thesis.degreeLevelPh.D.
kusw.oastatusna
kusw.oapolicyThis item does not meet KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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