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Papers In Press, published online ahead of print November 1, 2006
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Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5
Corresponding Author: trigatt{at}mcmaster.ca
The scavenger receptor, class B, type I (SR-BI) is a multiligand receptor that mediates binding and internalization of a variety of lipoprotein and non-lipoprotein ligands. Studies in gene-targeted and transgenic mice have demonstrated that SR-BI plays an important role in mediating cellular HDL-selective lipid uptake, driving reverse cholesterol transport, an important mechanism by which HDL protects against atherosclerosis. HDL selective lipid uptake involves the selective internalization of the lipid portion of HDL without the net internalization of the entire particle. Understanding how SR-BI-mediated selective lipid uptake is regulated may shed light on new approaches to therapeutic intervention in atherosclerosis and heart disease. We have utilized a model cell system to explore the pathways involved in murine SR-BI mediated lipid uptake from and signaling in response to distinct lipoprotein ligands: the physiologic ligand, HDL and a model ligand, acetyl-LDL. We report that murine SR-BI mediates lipid uptake in Chinese hamster ovary-derived cells via distinct pathways (selective versus endocytic) that are dependent on the lipoprotein ligand (HDL versus acetyl-LDL). We also demonstrate that HDL and acetyl-LDL activate distinct signaling pathways involving protein kinase C and/or Akt and extracellular regulated kinase (ERK) activation. Furthermore we show that murine SR-BI mediated selective lipid uptake versus endocytic uptake are differentially regulated by protein kinase signaling pathways, possibly involving protein kinase C and phosphatidyl inositol 3 kinase (PI3K). The PKC activator, PMA and the PI3K inhibitor wortmannin increase the degree of murine SR-BI-mediated selective lipid uptake whereas a protein-kinase C inhibitor has the opposite effect. This data demonstrates for the first time that SR-BI’s selective lipid uptake activity can be acutely regulated by intracellular signaling cascades, some of which can originate from HDL binding to murine SR-BI itself.
Revised on September 22, 2006
Accepted on November 1, 2006
Regulation of SR-BI-mediated selective lipid uptake in Chinese hamster ovary-derived cells by protein kinase signaling pathways
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