The mechanism(s) underlying the dramatic reduction in the risk of coronary heart disease associated with ingestion of diets rich in Omega 3 fatty acids (Om3FA) are not known, nor has the question of whether Om3FA benefit patients with the common potent risk factor, hypercholesterolemia (HC), been examined systematically. We have observed in preliminary experiments in HC patients that Om3FA lower LDL, raise HDL2, and rduce the content of free cholesterol/lecithin ratio of the lipoproteins creating a gradient favoring the centripetal movement of cholesterol from cells to the liver. In this application, we propose to examine systematically mechanisms that underlie these and other possible antiatherogenic changes in lipoproteins: by first comparing both quantitatively and qualitatively the lipoprotein responses to two differing Om3FA preparations (ethyl esters, triglycerides), in patients with three defined forms of HC. We then plan to determine whether compositional changes we have already shown in lipoproteins modify their physicochemical characteristics (size, phase transition temperature, subpopulation distribution, fluidity), and functional properties (the LDL catabolic pathways, HDL's capacity to promote cholesterol efflux from cells and transfer cholesterol ester to other lipoproteins). Next, we will assess the effects of Om3FA on the composition of plasma neutral and phospholipids and their molecular species, and on four key regulatory enzymes in lipoprotein metabolism (lipoprotein lipase, hepatic lipase, LCAT and lysolecithin acyl transferase). Hep G2 cells will be employed to determine whether Om3FA inhibit hepatic apoprotein B and triglyceride synthesis. Since Om3FA are incorporated into membranes through exchange reactions and biogenesis, we propose to examine their effects on certain critical membrane functions such as 1) the capacity to metabolize LDL; 2) the activities of plasma membrane-bound enzymes and receptors; and 3) the efflux of free cholesterol from cultured cells. This comprehensive experimental approach should provide detailed new information about the biological actions of Om3FA on lipoprotein metabolism, crucial to understanding how they reduce cardiovascular risk, and yield practical insights as to whether dietary supplementation can benefit patients with HC.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039194-04
Application #
3355866
Study Section
Special Emphasis Panel (SRC (24))
Project Start
1987-07-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1992-04-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Brown, E R; Subbaiah, P V (1994) Differential effects of eicosapentaenoic acid and docosahexaenoic acid on human skin fibroblasts. Lipids 29:825-9
Subbaiah, P V; Rodby, R A (1994) Abnormal acyltransferase activities and accelerated cholesteryl ester transfer in patients with nephrotic syndrome. Metabolism 43:1126-33
Subbaiah, P V; Kaufman, D; Bagdade, J D (1993) Incorporation of dietary n-3 fatty acids into molecular species of phosphatidyl choline and cholesteryl ester in normal human plasma. Am J Clin Nutr 58:360-8
Subbaiah, P V; Liu, M; Bolan, P J et al. (1992) Altered positional specificity of human plasma lecithin-cholesterol acyltransferase in the presence of sn-2 arachidonoyl phosphatidyl cholines. Mechanism of formation of saturated cholesteryl esters. Biochim Biophys Acta 1128:83-92
Bagdade, J D; Ritter, M C; Davidson, M et al. (1992) Effect of marine lipids on cholesteryl ester transfer and lipoprotein composition in patients with hypercholesterolemia. Arterioscler Thromb 12:1146-52
Liu, M; Krul, E S; Subbaiah, P V (1992) Effect of apoprotein B conformation on the activation of lysolecithin acyltransferase and lecithin: cholesterol acyltransferase. Studies with subfractions of low density lipoproteins. J Biol Chem 267:5139-47
Bagdade, J D; Ritter, M C; Subbaiah, P V (1991) Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia. J Clin Invest 87:1259-65
Davidson, M H; Burns, J H; Subbaiah, P V et al. (1991) Marine oil capsule therapy for the treatment of hyperlipidemia. Arch Intern Med 151:1732-40
Subbaiah, P V; Norum, R A; Bagdade, J D (1991) Effect of apolipoprotein activators on the specificity of lecithin:cholesterol acyltransferase: determination of cholesteryl esters formed in A-I/C-III deficiency. J Lipid Res 32:1601-9
Bagdade, J D; Kaufman, D; Ritter, M C et al. (1990) Probucol treatment in hypercholesterolemic patients: effects on lipoprotein composition, HDL particle size, and cholesteryl ester transfer. Atherosclerosis 84:145-54

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