title: Studies in mice, hamsters, and rats demonstrate that repression of hepatic apoA-I expression by taurocholic acid in mice is not mediated by the farnesoid-X-receptor.
abstract: It is claimed that apoA-I expression is repressed in mice by cholic acid (CA) and its taurine conjugate, taurocholic acid (TCA) via farnesoid X receptor (FXR) activation. We measured apoA-I expression in mice, hamsters, and rats treated with highly potent and selective synthetic FXR agonists or with TCA. All of the synthetic agonists bound to FXR with high affinity in a scintillation proximity assay. However, TCA did not compete with the radioligand up to the highest concentration used (100 μM). The C-site regulatory region of apoA-I, through which FXR has been reported to regulate its expression, is completely conserved across the species investigated. In both male and female human apoA-I-transgenic mice, we reproduced the previously reported strong inhibition of human apoA-I expression upon treatment with the typical supraphysiological dose of TCA used in such studies. However, in contrast to some previous reports, TCA did not repress murine apoA-I expression in the same mice. Also, more-potent and -selective FXR agonists did not affect human or murine apoA-I expression in this model. In LDL receptor-deficient mice and Golden Syrian hamsters, selective FXR agonists did not affect apoA-I expression, whereas in Wistar rats, some even increased apoA-I expression. In conclusion, selective FXR agonists do not repress apoA-I expression in rodents. Repression of human apoA-I expression by TCA in transgenic mice is probably mediated through FXR-independent mechanisms.
authors.affiliation: Departments of Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland. Electronic address: christophe.gardes@roche.com.
authors.forename: Christophe
authors.initials: C
authors.lastname: Gardès
authors.affiliation: Departments of Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Blum
authors.affiliation: Chemistry, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Bleicher
authors.affiliation: Departments of Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Chaput
authors.affiliation: Bio-informatics, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Departments of Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Hartman
authors.affiliation: Departments of Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Handschin
authors.affiliation: Chemistry, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Richter
authors.affiliation: Departments of Metabolic Diseases, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: G Martin
authors.initials: GM
authors.lastname: Benson
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D017124:Conserved Sequence; D006224:Cricetinae; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012588:Scintillation Counting; D013045:Species Specificity; D013656:Taurocholic Acid / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016632:Apolipoprotein A-I; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013656:Taurocholic Acid; D000099150:Receptor, Farnesoid X-Activated