The objective of the proposed work is to characterize the mechanisms whereby IV lipid emulsions deliver TG to tissues and cells and subsequently influence cell lipid deposition and metabolism. A major new hypothesis is that emulsion remnants are the key vehicle for delivery of a substantial fraction of emulsion TG-FA to tissues and that these pathways are especially important for uptake of LC-FA and VLC-FA. A comprehensive set of thematically linked in vitro and in vivo approaches is proposed to explore the mechanisms whereby emulsion TG, size, and apoE influence emulsion clearance from plasma, entry into cells, and metabolism within cells. Studies using 13C-NMR will define lipid properties and circular dichroism and anti apoE monoclonal antibody immunoreactivity studies (to study conformation at different regions of apoE) will delineate how lipid composition and particle size determine physical properties of lipids and apo E (Aim 1). Cell culture models will be used to define how characteristics of the emulsion, the cell, and released FA interact to regulate emulsion particle uptake and intracellular TG and cholesterol homeostasis (Aim 2). Emulsion infusions into genetically mutant mice will define the contributions of emulsion TG composition, size, and apoE, and of lipases to particle clearance from plasma, targeting to different tissues by receptor and non-receptor pathways, and cell lipid metabolism (Aim 3).
Aim 4 will compare pathways of clearance of IV lipid emulsions containing long, medium or n-5 VLC-FA in humans, distinguishing among mechanisms requiring release of TG as FFA in plasma and those involving direct emulsion uptake into cells. Since emulsion clearance is often retarded in subjects receiving IV nutrition, these studies will provide the new understanding required to optimize delivery of specific FAs to target tissues in patients on IV nutrition.
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