Date of Award

12-2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Supervisor

Professor B.L. Trigatti

Abstract

Lipids are essential molecules for cellular function; they are required for energy production, membrane structure, and can serve as signaling molecules. Normal metabolism requires cellular uptake and efflux as well as intercellular transport of lipids. Disruption of these events can lead to pathological processes like obesity and atherosclerosis. Transport of lipids between tissues involves moving hydrophobic species through a polar environment. This is achieved by carrier mediated lipid transport. These carriers can have significant impact on cellular uptake and efflux of lipids. This thesis investigated carrier mediated lipid transport in two situations, 1) long chain fatty acids (LCF As) and the carrier protein albumin, and 2) cholesterol (and other lipids) carried by high density lipoprotein particles. Significant issues regarding cellular LCF A uptake from albumin remain unresolved. 1) How do LCF As traverse the plasma membrane, and 2) is an albumin receptor involved in LCF A uptake? With respect to the first question, we hypothesized that the mechanism of LCFA uptake may be sensitive to cellular cholesterol. Our studies concluded that cholestrol-depleting agents inhibit LCFA uptake but not that of a non-carrier mediated subtrate. In regard to the second question, we investigated if albumin binding proteins exist on the cell surface of adipocytes. We found that albumin binding activity increased as cells undergo adipogenesis, and candidate proteins for this activity were found. We also investigated the role of the high density lipoprotein (HDL) receptor, scavenger receptor class B type I (SR-BI) in cholesterol metabolism and atherosclerosis. SR-BI has been found to be atheroprotective in mice, and this may involve cholesterol efflux from macrophage foam cells to HDL. We investigated the affect of bone marrow specific ablation ofSR-BI on atherosclerosis in mice. We concluded that SR-BI expression in bone marrow- erived cells can protect against atherosclerosis in the absence of any changes in overall lipoprotein metabolism. concluded that cholesterol-depleting agents inhibit LCF A uptake but not that of a noncarrier mediated substrate. In regard to the second question, we investigated if albumin binding proteins exist on the cell surface of adipocytes. We found that albumin binding

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