title: FGF19 signaling cascade suppresses APOA gene expression.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Institute of Molecular Biology and Biochemistry, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Indumathi
authors.initials: I
authors.lastname: Chennamsetty
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Karam M
authors.initials: KM
authors.lastname: Kostner
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Gert M
authors.initials: GM
authors.lastname: Kostner
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D001054:Apolipoproteins A; C117476:FGF19 protein, human; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors