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Papers In Press, published online ahead of print February 1, 2007
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* Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
Departments of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario, Canada
Departments of Biology and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of videos.
Published, JLR Papers in Press, November 1, 2006.
1 To whom correspondence should be addressed. e-mail: trigatt{at}mcmaster.ca
Scavenger receptor, class B, type I (SR-BI) mediates binding and internalization of a variety of lipoprotein and nonlipoprotein ligands, including HDL. Studies in genetically engineered mice revealed that SR-BI plays an important role in HDL reverse cholesterol transport and protection against atherosclerosis. Understanding how SR-BI's function is regulated may reveal new approaches to therapeutic intervention in atherosclerosis and heart disease. We utilized a model cell system to explore pathways involved in SR-BI-mediated lipid uptake from and signaling in response to distinct lipoprotein ligands: the physiological ligand, HDL, and a model ligand, acetyl LDL (AcLDL). In Chinese hamster ovary-derived cells, murine SR-BI (mSR-BI) mediates lipid uptake via distinct pathways that are dependent on the lipoprotein ligand. Furthermore, HDL and AcLDL activate distinct signaling pathways. Finally, mSR-BI-mediated selective lipid uptake versus endocytic uptake are differentially regulated by protein kinase signaling pathways. The protein kinase C (PKC) activator PMA and the phosphatidyl inositol 3-kinase inhibitor wortmannin increase the degree of mSR-BI-mediated selective lipid uptake, whereas a PKC inhibitor has the opposite effect. These data demonstrate 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.
Supplementary key words acetyl LDL • endocytosis • HDL • lipoprotein • phosphatidyl inositol 3-kinase • protein kinase C • scavenger receptor, class B, type I
Abbreviations: AcLDL, acetyl LDL; apo, apolipoprotein; CHO, Chinese hamster ovary; CTX-B, cholera toxin subunit B; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; ERK, extracellular signal-regulated kinase; KFM, potassium-free medium; MAPK, mitogen-activated protein kinase; MARCKS, myristoylated alanine-rich C-kinase substrate; mSR-AI, murine scavenger receptor, class A, type I; mSR-BI, murine scavenger receptor, class B, type I; PI3K, phosphatidyl inositol 3-kinase; PKC, protein kinase C; SR-AI, scavenger receptor, class A, type I; SR-BI, scavenger receptor, class B, type I
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