Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/11219
Title: | Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli |
Authors: | Wang, David Yu Chang |
Advisor: | Trigatti, Bernardo L. Igdoura, Suleiman A. Truant, Ray |
Department: | Biochemistry |
Keywords: | Atherosclerosis receptor cholesterol inflammation macrophage lipoprotein;Biochemistry;Biology;Cell Biology;Immunity;Medical Biochemistry;Medical Cell Biology;Medical Molecular Biology;Medical Sciences;Molecular Biology;Biochemistry |
Publication Date: | Oct-2011 |
Abstract: | <p>In atherosclerotic plaques, macrophages ingest modified LDL and turn to foam cells. Others have shown that SR-BI expression levels inversely correlated with cellular cholesterol levels, and is independent of well characterized cholesterol sensing pathways; SREBP and LXR. Thus the mechanism of regulation of SR-BI is unclear. In this study, we showed that treating macrophage with agents known to increase cellular cholesterol levels, namely acLDL, LDL, MβCD:Cholesterol, resulted in reduction in HMGCoAR mRNA and SR-BI expression levels. In contrast, acLDL did not reduce SR-BI mRNA levels in macrophages from acLDL SR-A KO mice, demonstrating that acLDL mediate suppression of SR-BI was dependent on SR-A. Fucoidan, a known competitive inhibitor of acLDL binding to SR-A, and subsequent degradation, also suppressed SR-BI expression levels. Unlike acLDL, however, fucoidan induced mRNA levels corresponding to the pro-inflammatory genes iNOS and IL-6 mRNA levels, and its effects were not altered by the lack of SR-A. Instead, fucoidan mediated stimulation of iNOS and IL-6 and suppression of SR-BI mRNA levels was prevented by an anti-CD14 blocking antibody, demonstrating that the fucoidan mediated effects were dependent on CD14. Interleukin-15, a pro-inflammatory cytokine that binds to a distinct receptor, also induced iNOS and IL-6 mRNA levels and reduced SR-BI expression, suggesting that inflammatory signaling in general can reduce SR-BI expression levels. Treatment of macrophages with the lipoproteins acLDL, LDL or HDL suppressed the induction of iNOS and IL-6 mRNA by fucoidan or IL-15. Macrophages foam cells in an atherosclerotic plaque may have reduced SR-BI due to exposure with modified LDL or inflammatory cytokines or both in an atherosclerotic plaque. SR-BI expression in macrophages protects against atherosclerosis development. Our data suggests that modified lipoproteins as well as inflammatory stimuli suppress SR-BI expression in macrophages and this may contribute to their pro-apoptotic properties.</p> |
URI: | http://hdl.handle.net/11375/11219 |
Identifier: | opendissertations/6203 7209 2245848 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Size | Format | |
---|---|---|---|
fulltext.pdf | 995.53 kB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.