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LDL immune complexes stimulate LDL receptor expression in U937 histiocytes via extracellular signal-regulated kinase

Yuchang Fu1, Yan Huang, Sumita Bandyopadhyay

  • 1Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC 29401, USA.

Journal of Lipid Research
|May 6, 2003
PubMed

Insights

Low-density lipoprotein-containing immune complexes (LDL-ICs) increase LDL receptor (LDLR) expression in macrophages. This occurs through the ERK signaling pathway and AP-1 transcription factor activation, not sterol-regulatory element binding proteins.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Low-density lipoprotein-containing immune complexes (LDL-ICs) are known to up-regulate LDL receptor (LDLR) expression in human macrophages.
  • Understanding the precise molecular mechanisms and signaling pathways involved is crucial for elucidating cellular lipid metabolism and immune responses.

Purpose of the Study:

  • To investigate the molecular mechanisms by which LDL-ICs up-regulate LDLR expression.
  • To identify the specific signaling pathways mediating LDLR up-regulation induced by LDL-ICs.

Main Methods:

  • Treatment of U937 histiocytes with LDL-ICs.
  • Analysis of sterol-regulatory element binding proteins (SREBPs) precursors and cleaved forms.
  • Promoter deletion and mutation studies for LDLR gene.
  • Electrophoretic mobility shift assays (EMSA) to assess transcription factor activity.
  • Investigation of extracellular signal-regulated kinase (ERK) signaling pathway.

Main Results:

  • LDL-ICs did not alter SREBP-1a or SREBP-2 levels, suggesting SREBPs are not involved in this process.
  • AP-1 binding sites in the LDLR promoter were essential for LDL-IC-stimulated expression.
  • LDL-ICs enhanced AP-1 transcription factor activity.
  • LDLR up-regulation by LDL-ICs was dependent on the ERK signaling pathway.

Conclusions:

  • LDL-ICs up-regulate LDLR expression in macrophages.
  • The mechanism involves ERK signaling pathway activation.
  • Transcriptional activation is mediated through AP-1 motifs.

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