The high density lipoprotein (HDL) receptor Scavenger Receptor, Class B, Type I (SRBI)
is a 509 amino acid integral membrane protein which has been shown to have an
important role in HDL-mediated reverse cholesterol transport. SR-BI has been shown to
mediate selective uptake of cholesterol, and also mediates efflux of cholesterol to HDL as
seen in in vitro cell culture studies. SR-BI is abundant in the liver and steroidogenic
tissues, and is also present in macrophages, which play an important role in the initial
stages of atherosclerotic development. SR-BI has been shown to be protective against
atherosclerosis by way of overexpression and knockout (KO) studies in murine
atherosclerosis models, including low density lipoprotein receptor (LDLR) knockout
mice, apolipoprotein E (ApoE) knockout mice, and human apolipoprotein B (ApoB)
transgenic mice. SR-BI/LDLR double knockout (dKO) mice show a 6-fold increase in
diet-induced atherosclerosis compared to LDLR single KO controls, and SR-BI/ApoE
dKO mice show severe coronary occlusion, myocardial infarction, and premature death
on a normal chow diet. In both, plasma total cholesterol levels are significantly elevated,
and associated with abnormally large HDL particles. The majority ofSR-BI's
atheroprotective effect has been shown to result from plasma cholesterol clearance by
way of selective uptake in the liver. Recently, Covey et al showed that elimination of SRBI
expression in macrophages of LDLR KO mice resulted in increased diet-induced
atherosclerosis. To see if SR-BI in macrophages contributes to the overall
atheroprotective effect of SR-BI in ApoE KO mice, presumably by mediating cellular
cholesterol efflux to HDL, selective deletion ofSR-BI was induced in bone marrow
derived cells of ApoE KO mice using bone marrow transplantation. Female ApoE -/recipient
mice were transplanted with either SR-BI +/+ ApoE -/-or SR-BI -/- ApoE -/bone
marrow from male donor mice, and fed a high fat diet for 12 weeks. This resulted in
significantly increased atherosclerosis in mice transplanted with SR-BI -/- ApoE -/-bone
marrow, with a concomitant decrease in cholesterol associated with HDL-sized
lipoproteins. No significant differences were seen in plasma total cholesterol levels or
levels of cholesterol associated with non-HDL lipoproteins. These data suggest that SRBI
in macrophages contributes to SR-BI's overall protective effect against
atherosclerosis, and also plays a role in the regulation ofHDL cholesterol, in ApoE
deficient mice. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22770 |
| Date | 11 1900 |
| Creators | Risvi, Ali Amjad |
| Contributors | Trigatti, Bernardo L., Biochemistry |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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