Farnesoid X receptor represses hepatic human APOA gene expression

Chennamsetty, Indumathi, Claudel, Thierry, Kostner, Karam M., Baghdasaryan, Anna, Kratky, Dagmar, Levak-Frank, Sanja, Frank, Sasa, Gonzalez, Frank J., Trauner, Michael and Kostner, Gert M. (2011) Farnesoid X receptor represses hepatic human APOA gene expression. Journal of Clinical Investigation, 121 9: 3724-3734. doi:10.1172/JCI45277


Author Chennamsetty, Indumathi
Claudel, Thierry
Kostner, Karam M.
Baghdasaryan, Anna
Kratky, Dagmar
Levak-Frank, Sanja
Frank, Sasa
Gonzalez, Frank J.
Trauner, Michael
Kostner, Gert M.
Title Farnesoid X receptor represses hepatic human APOA gene expression
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
1558-8238
Publication date 2011-09
Sub-type Article (original research)
DOI 10.1172/JCI45277
Open Access Status DOI
Volume 121
Issue 9
Start page 3724
End page 3734
Total pages 11
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Collection year 2012
Language eng
Formatted abstract
High plasma concentrations of lipoprotein(a) [Lp(a), which is encoded by the APOA gene] increase an individual’s risk of developing diseases, such as coronary artery diseases, restenosis, and stroke. Unfortunately, increased Lp(a) levels are minimally influenced by dietary changes or drug treatment. Further, the development of Lp(a)- specific medications has been hampered by limited knowledge of Lp(a) metabolism. In this study, we identified patients suffering from biliary obstructions with very low plasma Lp(a) concentrations that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human APOA (tg-APOA mice) lowered plasma concentrations and hepatic expression of APOA. To test whether farnesoid X receptor (FXR), which is activated by bile acids, was responsible for the low plasma Lp(a) levels in cholestatic patients and mice, we treated tg-APOA and tg-APOA/Fxr–/– mice with cholic acid. FXR activation markedly reduced plasma concentrations and hepatic expression of human APOA in tg-APOA mice but not in tg-APOA/Fxr –/– mice. Incubation of primary hepatocytes from tg-APOA mice with bile acids dose dependently downregulated APOA expression. Further analysis determined that the direct repeat 1 element between nucleotides –826 and – 814 of the APOA promoter functioned as a negative FXR response element. This motif is also bound by hepatocyte nuclear factor 4α (HNF4α), which promotes APOA transcription, and FXR was shown to compete with HNF4α for binding to this motif. These findings may have important implications in the development of Lp(a)-lowering medications. 
Keyword Bile Acid Homeostasis
Coronary Heart Disease
Nuclear Receptor
Myocardial Infarction
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Medicine Publications
 
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