Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Chennamsetty, I.
Transcriptional Regulation of Apolipoprotein(a) The Role of Bile Acids
[ Dissertation ] Medical University of Graz; 2011. pp. 90
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- Autor*innen der Med Uni Graz:
- Chennamsetty Indumathi
- Betreuer*innen:
- Frank Sasa
- Höfler Gerald
- Kostner Gerhard
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- Abstract:
- Abstract High plasma concentrations of lipoprotein(a), [Lp(a)] which is encoded by the apo(a) gene has been implicated as a genetic risk factor for 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 found that patients suffering from biliary obstructions exhibit very low plasma Lp(a) concentrations that rise significantly after surgical intervention. Consistent with the latter phenomenon, common bile duct ligation in mice lowered plasma concentrations and hepatic expression of apo(a) drastically. To test whether the bile acid receptor FXR was responsible for low plasma Lp(a) levels in cholestatic patients and mice, we treated transgenic human apo(a) mice (tg-apo(a)) and tg-apo(a)/FXR-/- mice with cholic acid (CA). FXR activation resulted in a significant reduction of plasma concentrations and hepatic expression of human apo(a) in tg-apo(a) mice but not in tg-apo(a)/FXR-/- mice. Incubation of primary hepatocytes from tg-apo(a) mice with bile acids resulted in a dose dependent down regulation of apo(a) expression. Promoter transfection experiments, mutation analysis, gel shift assay and Chromatin immunoprecipitation (ChIP) assay demonstrated that the DR-1 element between nucleotides -826 and -814bp of the apo(a) promoter functioned as a negative FXR-response element. This motif is also occupied by hepatocyte nuclear factor 4¿ (HNF4¿), which promotes apo(a) transcription, and FXR was shown to compete with HNF4¿ for binding to this motif. In summary, our findings provide mechanistic insights in to the transcriptional regulation of human apo(a) by bile acids and its receptor FXR. These findings may have important implications in designing therapeutics for patients with elevated plasma Lp(a) levels and therefore at higher atherothrombotic risk.