Submitted on October 21, 2002
Revised on April 21, 2003
Accepted on April 21, 2003
LDL immune complexes stimulate low density lipoprotein receptor expression in U937 histiocytes via extracellular signal-regulated kinase and AP-1
Yuchang Fu, Yan Huang, Sumita Bandyopadhyay, Gabriel Virella, and Maria F. Lopes-Virella
Medicine Dept., Medical University of South Carolina, Charleston, SC 29403
Corresponding Author: virellam{at}musc.edu
We have previously shown that LDL-containing immune complexes (LDL-ICs) induce upregulation of LDL receptor (LDLR) expression in human macrophages. The present study further investigated the molecular mechanisms leading to LDLR upregulation by LDL-ICs as well as the signaling pathways involved. Results showed that treatment of U937 histiocytes with LDL-ICs did not increase the precursors and the cleaved forms of sterol-regulatory element binding protein (SREBP) 1a and 2, suggesting that SREBPs may not be involved in LDLR upregulation by LDL-ICs. Promoter deletion and mutation studies showed that the AP-1 binding sites were essential for LDL-IC-stimulated LDLR expression. Electrophoretic mobility shift assays further demonstrated that LDL-ICs stimulated transcription factor AP-1 activity. Studies assessing the signaling pathways involved in LDLR upregulation by LDL-ICs showed that the upregulation of LDLR was extracellular signal-regulated kinase (ERK)-dependent. In conclusion, the present study shows that LDL-ICs upregulate LDLR expression via the ERK signaling pathway and the AP-1 motif-dependent transcriptional activation.
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