FGF19 signaling cascade suppresses APOA gene expression

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.