METABOLISM OF INTRAVENOUS LIPID EMULSIONS

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The objective of this research program is to characterize how specific types of triglycerides (TG) in intravenous (IV) lipid emulsions affect particle metabolism and impact upon the biological potentials of their component lipids. These emulsions also serve as models for triglyceride-rich particles (TGRP) such as chylomicrons and VLDL. In the past, our findings not only contributed to delineating cellular pathways and mechanisms affected by different fatty acids (FA) but were also translated into changing practices of IV nutrition. We initially focused upon differences between long chain TG (LCT) and median chain TG (MCT); in the past 5 years our emphasis has been upon the long chain omega-3 (n-3) FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DMA). Based upon data from the current funding period, we can hypothesize that addition of n-3 TG to TGRP changes their metabolism and tissue delivery away from classical" pathways used for n-6 TGRP clearance (such as those involving intravascular lipolysis, the LDL receptor, and apoprotein E) to "non-classical" metabolic pathways involving cell surface proteoglycans (PG), anchoring to cell surfaces, and lipoprotein lipase (LpL). This hypothesis will be studied in experiments in Aim 1 where we will examine in vitro, using NMR, how n-3 FA and n-3 TG affects model phospholipid membranes, and then how this determines n-3 TG metabolism in cultured cells. Aim 1 will also utilize normal and mutant mouse models to define the roles of "non-classical" pathways in vivo, for example, by utilizing mice with specific LpL mutations. Based upon our recent data that n-3 FA chronic administration markedly diminishes LDL and LDL-cholesterol delivery to the arterial wall in mouse models in vivo, we hypothesize that these effects link to changing distribution and expression of LpL in the arterial wall, and that this will be related to alterations in patterns of gene expression of arterial wall macrophages, dendritic cells and other arterial cells, each to be tested under experiments in Aim 2. Our experiments using acute IV infusions of lipid emulsions and chronic feeding regimens in varying mouse models will test the hypothesis that n-3 FA are particularly potent in diminishing adverse mechanisms that contribute to early atherogenesis by programming responses away from proinflammatory towards anti-inflammatory pathways and that these changes link to decreasing cholesterol delivery and modulating LpL expression in the arterial wall. Our studies will allow new insights as to how n-3 FA are delivered to target organs and act as bioactive modulators to alter the pathways and change expression of specific genes to reduce adverse changes involved at the early states atherogenesis. The objective of this research program is to characterize how specific types of triglycerides (TG) in intravenous (IV) lipid emulsions affect particle metabolism and impact upon the biological potentials of their component lipids. These emulsions also serve as models for triglyceride-rich particles (TGRP) such as chylomicrons and VLDL. In the past, our findings not only contributed to delineating cellular pathways and mechanisms affected by different fatty acids (FA) but were also translated into changing practices of IV nutrition. We initially focused upon differences between long chain TG (LCT) and median chain TG (MCT); in the past 5 years our emphasis has been upon the long chain omega-3 (n-3) FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DMA). Based upon data from the current funding period, we can hypothesize that addition of n-3 TG to TGRP changes their metabolism and tissue delivery away from classical" pathways used for n-6 TGRP clearance (such as those involving intravascular lipolysis, the LDL receptor, and apoprotein E) to "non-classical" metabolic pathways involving cell surface proteoglycans (PG), anchoring to cell surfaces, and lipoprotein lipase (LpL). This hypothesis will be studied in experiments in Aim 1 where we will examine in vitro, using NMR, how n-3 FA and n-3 TG affects model phospholipid membranes, and then how this determines n-3 TG metabolism in cultured cells. Aim 1 will also utilize normal and mutant mouse models to define the roles of "non-classical" pathways in vivo, for example, by utilizing mice with specific LpL mutations. Based upon our recent data that n-3 FA chronic administration markedly diminishes LDL and LDL-cholesterol delivery to the arterial wall in mouse models in vivo, we hypothesize that these effects link to changing distribution and expression of LpL in the arterial wall, and that this will be related to alterations in patterns of gene expression of arterial wall macrophages, dendritic cells and other arterial cells, each to be tested under experiments in Aim 2. Our experiments using acute IV infusions of lipid emulsions and chronic feeding regimens in varying mouse models will test the hypothesis that n-3 FA are particularly potent in diminishing adverse mechanisms that contribute to early atherogenesis by programming responses away from proinflammatory towards anti-inflammatory pathways and that these changes link to decreasing cholesterol delivery and modulating LpL expression in the arterial wall. Our studies will allow new insights as to how n-3 FA are delivered to target organs and act as bioactive modulators to alter the pathways and change expression of specific genes to reduce adverse changes involved at the early states atherogenesis.