In addition to tissue-derived oxidized lipids (Ox-lip), diet is also a major source of Ox-lip. Despite the suggestion that dietary Ox-lip might contribute to atherosclerosis, very little is known regarding their uptake and mechanism by which they contribute to atherosclerosis. The applicant group recently demonstrated that oxidized fatty acids (Ox-FFA) such as 13-hydroperoxy and hydroxy-linoleic acids are poorly taken up by cultured vascular smooth muscle cells (VSMC) and are extensively metabolized to hydrogen peroxide intracellularly. The PI has hypothesized that intestinal cells take up Ox-lip more effectively than other types of cells. This is based on the fact that, unlike other cells, the process of lipid uptake by the intestine involves micellarization of luminal contents and a passive diffusion of fatty acid products across the microvillus membrane. Secondly, unlike other cells, the intestinal villus cells contain special structures that increase surface area that might facilitate a rapid uptake of Ox-FFA. These factors would increase the rates of adsorption of Ox-FFA by intestinal cells relatively and hence become a major risk factor for cardiovascular disease.
Three Specific Aims have been proposed that will use radioactively labeled lipids and a variety of in vitro intestinal cell culture models and in vivo animal models of atherosclerosis to determine the metabolic fate, extent of uptake, and the extent of re-utilization of Ox-FFA for lipid synthesis in the enterocytes. The studies will also determine the contribution of Ox-lip to the assembly of the chylomicron and the atherogenic process.
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