Elevated plasma triglycerides (TG) and TG-rich lipoproteins (TGRLP), especially postprandial (pp) TGRLP, are emerging risk factors for atherothrombotic disease. However, little is known about the molecular basis for their interaction with cells of the artery wall or in the periphery. We identified and cloned a wholly unique receptor for dietary ppTGRLP, the apoB48 receptor (apoB48R), found in human monocyte-macrophages and in foam cells in arterial lesions. Now a mouse model, deficient in this receptor, has been created, and evidence demonstrates that in an atherogenic background the loss of the apoB48R reduces atherosclerosis significantly, further implicating it in macrophage foam cell formation and reduces peripheral uptake in tissues that normally express the receptor and elevates plasma cholesterol and triglycerides (TG). Therefore, using this new mouse model, we plan to determine its role in dietary lipoprotein metabolism and ppTGRLP uptake by cells in the periphery where the receptor is highly expressed (bone marrow, spleen, skeletal muscle and adipose). Furthermore, we will identify the molecular mechanisms and the extent to which ppTGRLP are atherogenic in mouse models of atherogenesis, including the apoE- and LDL R-deficient mice, crossed into the apoB48R-deficient mouse and in our newly developed apoB48R transgenic mice with enhanced tissue specific apoB48R expression in macrophages and liver (where it is not normally found) and we will evaluate the impact of the apoB48R on atherogenesis when animals are subjected to atherogenic and TG-elevating diets, thereby altering the postprandial mileau. We further plan to determine in vitro the molecular and cellular mechanisms by which the apoB48 R operates, that is, rapid, efficient accumulation of intracellular lipid. In vitro studies will identify the receptor recycling rates, endosomal/lysosomal trafficking, possible involvement of microtubules and/or microfilaments and rates of synthesis and degradation. The ligand-binding domain of the receptor will be sought as an eventual targeting site for intervention. Finally we will identify potential additional modifiers of macrophage pathobiology that may be exacerbated by the uptake of ppTGRLP via the apoB48R pathway by interfering in the normal cholesterol homeostasis, both production (HMGCoA reductase) and efflux (via ABC A1). The proposal uses the powerful techniques of mouse genetics coupled with dietary manipulations in vivo coupled with cell and molecular biology approaches in vitro aimed to answer key questions about the role of the apoB48 R and its interaction with ppTGRLP in health and disease.
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