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FGF19 signaling cascade suppresses APOA gene expression

Indumathi Chennamsetty1, Thierry Claudel, Karam M Kostner

  • 1Institute of Molecular Biology and Biochemistry, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.

Arteriosclerosis, Thrombosis, and Vascular Biology
|January 24, 2012
PubMed
Abstract

Insights

Fibroblast growth factor 19 (FGF19) reduces apolipoprotein(a) (APOA) levels by downregulating its hepatic expression. FGF19 targets the APOA promoter via FGFR4 and ERK1/2 signaling, offering potential therapeutic avenues for hyperlipoproteinemia.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Lipoprotein(a) is a key atherogenic particle with poorly understood metabolism.
  • Elevated lipoprotein(a) is a risk factor for cardiovascular disease.
  • Current therapies lack safe and effective methods to lower lipoprotein(a) levels.

Purpose of the Study:

  • To investigate the molecular mechanisms regulating apolipoprotein(a) (APOA) biosynthesis.
  • To explore the potential of fibroblast growth factor 19 (FGF19) in modulating APOA levels.

Main Methods:

  • Utilized transgenic human APOA mice (tg-APO mice) and primary hepatocyte cultures.
  • Administered recombinant human FGF19 and employed ERK1/2 phosphorylation inhibitors.
  • Investigated FGF19 receptor 4 (FGFR4) involvement using siRNA.
  • Conducted promoter reporter assays, mutation analysis, gel shift, and ChIP assays to identify regulatory elements.

Main Results:

  • FGF19 administration significantly reduced plasma APOA and hepatic APOA expression in tg-APO mice.
  • FGF19 induced ERK1/2 phosphorylation in hepatocytes, leading to APOA downregulation.
  • FGF19's effect was dependent on FGFR4 and ERK1/2 signaling.
  • An Ets-1 binding element in the APOA promoter, acting as an Elk-1 site, mediates FGF19-induced repression.

Conclusions:

  • FGF19 transcriptionally regulates human APOA expression through the FGFR4/ERK1/2 pathway.
  • Identified a specific binding site on the APOA promoter involved in this regulation.
  • Findings offer mechanistic insights for developing therapeutics for hyperlipoproteinemia.

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