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Lipopolysaccharide downregulates CD91/low-density lipoprotein receptor-related protein 1 expression through SREBP-1

P Costales1, J Castellano, E Revuelta-López

  • 1Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Barcelona, Spain.

Atherosclerosis
|January 15, 2013
PubMed

Insights

Lipopolysaccharide (LPS) reduces low-density lipoprotein receptor-related protein (LRP1) expression in macrophages by increasing Sterol regulatory element-binding protein-1 (SREBP-1). SREBP-1 mediates this LPS effect, independent of lipoproteins.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Sterol regulatory element-binding proteins (SREBPs) are known to negatively regulate CD91/low-density lipoprotein receptor-related protein (LRP1) expression.
  • LRP1 is a crucial receptor involved in endocytosis and signaling, mediating the uptake of numerous ligands.
  • Understanding the regulation of LRP1 is vital for comprehending cellular lipid metabolism and immune responses.

Purpose of the Study:

  • To investigate whether lipopolysaccharide (LPS) regulates LRP1 expression via SREBPs in human monocyte-derived macrophages (HMDM).
  • To elucidate the specific role of SREBP isoforms in mediating the effects of LPS and lipoproteins on LRP1 expression.

Main Methods:

  • Human monocyte-derived macrophages (HMDM) were treated with varying doses and durations of LPS.
  • Quantitative real-time PCR (qPCR) was used to measure mRNA levels of LRP1 and SREBP isoforms.
  • Western blotting was employed to assess protein levels of LRP1 and nuclear SREBP-1.
  • Specific silencing of SREBP-1 was performed using gene silencing techniques.

Main Results:

  • LPS treatment dose- and time-dependently inhibited LRP1 mRNA and protein expression in HMDM.
  • LPS significantly upregulated SREBP-1 mRNA and nuclear protein levels.
  • Silencing SREBP-1 prevented the LPS-induced reduction in LRP1 expression.
  • Native and aggregated LDL downregulated SREBP-2 and increased LRP1, but did not alter the LPS effect on SREBP-1 and LRP1.

Conclusions:

  • SREBP-1 acts as a key mediator for the downregulatory effect of LPS on LRP1 expression in human macrophages.
  • Lipoproteins and LPS modulate LRP1 expression through distinct SREBP isoforms (SREBP-2 and SREBP-1, respectively).
  • The regulatory effect of LPS on LRP1 is independent of the presence or modification state of LDL.

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