Icosanoids are potent biologic mediators derived from a specifically designated pool of fatty acids known as icosanoid-precursor fatty acids. Inhibition of icosanoid production by aspirin has been shown to reduce inflammation and the risk of thrombosis leading to stroke and myocardial infarction. For the last 5 years our laboratory has been investigating the molecular mechanisms by which arachidonate, the principal icosanoid precursor fatty acid, is converted to icosanoids, with the intention of identifying new regulatory steps which might be susceptible to pharmacologic intervention. In an effort to continue this work, this proposal also describes experiments intended to increase our understanding of the molecular events in the conversion of arachidonate and other icosanoid-precursor fatty acids to icosanoids. However, where our previous work focused exclusively on cellular fatty acid metabolism, the goals of the proposed work are to determine 1) the molecular mechanisms by which fatty acids are delivered to cells from triacylglycerol, phospholipids, and cholesterol esters in lipoproteins and from the nonesterified fatty acid pool bound to albumin and 2) how the particular route of delivery of fatty acid to cells effects its distribution within membranes of the cell and its metabolic fate inside the cells. Our first major objective is to determine which fatty acid-containing moieties within lipoproteins containing icosanoid precursor fatty acids actually deliver these fatty acids to cells (endothelial cells, platelets, and Hep G2 cells). Within this first objective, we will compare delivery of fatty acids to cells from the different lipoprotein moieties vs free fatty acid bound to albumin. Our second major objective is to determine whether the fate of icosanoid precursor fatty acids in cells, in terms of subcellular distribution (in Hep G2 cells), availability for icosanoid production (by endothelial cells and platelets), or packaging into newly synthesized lipoproteins (by Hep G2 cells), is dependent on the moiety which delivers the fatty acid to the cell. This series of aims, a logical extension of our previous work, will provide missing details on the molecular events by which icosanoid precursor fatty acids are transported in the plasma and delivered to cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK037454-05A3
Application #
3236375
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1986-08-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Muszbek, L; Haramura, G; Cluette-Brown, J E et al. (1999) The pool of fatty acids covalently bound to platelet proteins by thioester linkages can be altered by exogenously supplied fatty acids. Lipids 34 Suppl:S331-7
Kabakibi, A; Morse, C R; Laposata, M (1998) Fatty acid ethyl esters and HepG2 cells: intracellular synthesis and release from the cells. J Lipid Res 39:1568-82
Kabakibi, A; Vamvakas, E C; Cannistraro, P A et al. (1998) Collagen-induced whole blood platelet aggregation in patients undergoing surgical procedures associated with minimal to moderate blood loss. Am J Clin Pathol 109:392-8
Bird, D A; Kabakibi, A; Laposata, M (1997) The distribution of fatty acid ethyl esters among lipoproteins and albumin in human serum. Alcohol Clin Exp Res 21:602-5
Saghir, M; Werner, J; Laposata, M (1997) Rapid in vivo hydrolysis of fatty acid ethyl esters, toxic nonoxidative ethanol metabolites. Am J Physiol 273:G184-90
Gorski, N P; Nouraldin, H; Dube, D M et al. (1996) Reduced fatty acid ethyl ester synthase activity in the white blood cells of alcoholics. Alcohol Clin Exp Res 20:268-74
Bird, D A; Laposata, M; Hamilton, J A (1996) Binding of ethyl oleate to low density lipoprotein, phospholipid vesicles, and albumin: a 13C NMR study. J Lipid Res 37:1449-58
Laposata, M; Szczepiorkowski, Z M; Brown, J E (1995) Fatty acid ethyl esters: non-oxidative metabolites of ethanol. Prostaglandins Leukot Essent Fatty Acids 52:87-91
Teruya, J; Cluette-Brown, J; Szczepiorkowski, Z M et al. (1995) Mode of transport of fatty acid to endothelial cells influences intracellular fatty acid metabolism. J Lipid Res 36:266-76
Bird, D A; Szczepiorkowski, Z M; Trace, V C et al. (1995) Low-density lipoprotein reconstituted with fatty acid ethyl esters as a physiological vehicle for ethyl ester delivery to intact cells. Alcohol Clin Exp Res 19:1265-70

Showing the most recent 10 out of 25 publications