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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Chennamsetty, I; Claudel, T; Kostner, KM; Trauner, M; Kostner, GM.
FGF19 signaling cascade suppresses APOA gene expression.
Arterioscler Thromb Vasc Biol. 2012; 32(5):1220-1227
Doi: 10.1161/ATVBAHA.111.243055
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- Führende Autor*innen der Med Uni Graz
- Chennamsetty Indumathi
- Kostner Gerhard
- Co-Autor*innen der Med Uni Graz
- Claudel Thierry
- Trauner Michael
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- Abstract:
- Objective-Lipoprotein(a) is a highly atherogenic lipoprotein, whose metabolism is poorly understood. Currently no safe drugs exists that lower elevated plasma lipoprotein(a) concentrations. We therefore focused on molecular mechanisms that influence apolipoprotein(a) (APOA) biosynthesis. Methods and Results-Transgenic human APOA mice (tg-APO mice) were injected with 1 mg/kg of recombinant human fibroblast growth factor 19 (FGF19). This led to a significant reduction of plasma APOA and hepatic expression of APOA. Incubation of primary hepatocytes of tg-APOA mice with FGF19 induced ERK1/2 phosphorylation and, in turn, downregulated APOA expression. Repression of APOA by FGF19 was abrogated by specific ERK1/2 phosphorylation inhibitors. The FGF19 effect on APOA was attenuated by transfection of primary hepatocytes with siRNA against the FGF19 receptor 4 (FGFR4). Using promoter reporter assays, mutation analysis, gel shift, and chromatin immune-precipitation assays, an Ets-1 binding element was identified at -1630/-1615bp region in the human APOA promoter. This element functions as an Elk-1 binding site that mediates repression of APOA transcription by FGF19. Conclusion-These findings provide mechanistic insights into the transcriptional regulation of human APOA by FGF19. Further studies in the human system are required to substantiate our findings and to design therapeutics for hyper lipoprotein(a). (Arterioscler Thromb Vasc Biol.2012;32:1220-1227.)
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apolipoproteins A - genetics
- Atherosclerosis - genetics
- Cells, Cultured -
- Disease Models, Animal -
- Female -
- Fibroblast Growth Factors - metabolism
- Gene Expression Regulation -
- Humans -
- Mice -
- Mice, Transgenic -
- Polymerase Chain Reaction -
- Promoter Regions, Genetic -
- RNA, Messenger - genetics
- Transcription, Genetic -
- Find related publications in this database (Keywords)
- apolipoproteins
- fibrinolysis
- gene expression
- lipoproteins
- molecular biology