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Opposite regulation of the human apolipoprotein M gene by hepatocyte nuclear factor 1 and Jun transcription factors

Ioanna Mosialou1, Konstantin Krasagakis, Dimitris Kardassis

  • 1Department of Basic Sciences, University of Crete Medical School, Heraklion 71003, Greece.

The Journal of Biological Chemistry
|April 2, 2011
PubMed

Insights

Inflammation alters high-density lipoprotein (HDL) function. This study reveals how inflammatory signals, via AP-1 transcription factors, repress apolipoprotein M (apoM) gene expression, impacting HDL maturation and atheroprotection.

Area of Science:

  • Molecular biology
  • Cardiovascular research
  • Gene regulation

Background:

  • High-density lipoprotein (HDL) possesses atheroprotective functions, but inflammation can render it pro-atherogenic.
  • Apolipoprotein M (apoM) is crucial for HDL maturation and possesses anti-atherosclerotic properties.
  • Pro-inflammatory signals down-regulate apoM gene expression, affecting HDL functionality.

Purpose of the Study:

  • To elucidate the molecular mechanism by which inflammation down-regulates apolipoprotein M (apoM) gene expression.
  • To investigate the role of transcription factors in mediating the inflammatory repression of the apoM promoter.
  • To understand how apoM regulation impacts HDL particle function during inflammation.

Main Methods:

  • Analysis of the human apoM promoter activity in HepG2 cells.
  • Electrophoretic mobility shift assays (EMSAs) to study transcription factor binding.
  • Reporter gene assays to assess promoter transactivation and repression.
  • Gene expression analysis following treatment with inflammatory stimuli or overexpression of specific transcription factors.

Main Results:

  • The human apoM promoter contains a regulatory element that binds both hepatocyte nuclear factor 1 (HNF-1) and AP-1 transcription factors (c-Jun, JunB).
  • Overexpression of c-Jun or JunB repressed apoM promoter activity, both basally and when HNF-1 was present.
  • Inflammatory stimuli (phorbol esters, PKCα) inhibited apoM gene expression in a manner dependent on c-Jun/JunB activity.
  • A competitive binding mechanism between HNF-1 and Jun proteins on the apoM promoter was identified.

Conclusions:

  • Inflammation represses apoM gene expression through a novel mechanism involving competitive binding of Jun proteins to the apoM promoter, displacing HNF-1.
  • This transcriptional repression by inflammatory signals affects apoM levels, potentially altering HDL maturation and atheroprotective functions.
  • The findings provide insights into the regulation of liver-specific apolipoprotein genes during inflammation and its impact on cardiovascular health.

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