Fish oils are unique dietary fats which powerfully lower both fasting and postprandial triglyceride levels in humans. Although inhibition of hepatic triglyceride synthesis is widely believed to be the reason for the reduction in fasting triglycerides, the reason why omega3 fatty acids (FAs) lower chylomicron levels is virtually unknown. The purpose of this project is to study the mechanism, and in so doing to evaluate two new methods to explore chylomicron metabolism in humans. We will study both humans and rats to determine whether chronic omega3 FA supplementation enhances chylomicron clearance or slows fat absorption/chylomicron secretion. Healthy volunteers (n=24) will be given clinically-relevant doses (5 g/d) of fatty acid ethyl esters. They will take an olive oil placebo for 4 weeks and then be randomly and blindly assigned to take either safflower oil (omega6 PUFA control) or a fish oil concentrate (containing 64% EPA+DHA) for the next 4 weeks. During the placebo and the active treatment phases we will test the absorption hypothesis (by intestinal perfusion to measure fat absorption over a length small bowel, and stool collection after an oral fat load to look for fat malabsorption), and the clearance hypothesis (by injection of autologous, chemically-labeled chylomicrons to measure clearance kinetics, and measurement of endogenous lipoprotein and hepatic lipase activities). We will also determine the effect of omega3 FAs on fractional cholesterol absorption. Studies in rats will examine the same hypotheses, only more invasively. Fat absorption will be assessed by quantitative lymphatic drainage after a high fat meal and by accumulation of labeled chylomicrons in the plasma during lipolytic blockade using Triton WR1339+ethyl oleate. Homologous and heterologous chylomicrons will be injected into control and omega3 FA fed rats and their clearance rates determined. Chylomicrons will also be injected into functionally hepatectomized rats to assess how rapidly they are converted into remnants, and into isolated livers to determine their rate of hepatic remnant uptake. These studies should reveal the mechanism behind the remarkable postprandial hypochylomicronemia observed in humans taking omega3 FAs. They should also produce a new method for studying LpL activity in vivo in humans. Future studies will explore the molecular mechanisms responsible for the omega3 FA-induced reduction in chylomicron levels.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047468-04
Application #
2735194
Study Section
Nutrition Study Section (NTN)
Project Start
1995-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Missouri Kansas City
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Park, Yongsoon; Jones, Philip G; Harris, William S (2004) Triacylglycerol-rich lipoprotein margination: a potential surrogate for whole-body lipoprotein lipase activity and effects of eicosapentaenoic and docosahexaenoic acids. Am J Clin Nutr 80:45-50
Park, Yongsoon; Harris, William S (2003) Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res 44:455-63
Park, Yongsoon; Schoene, Norberta; Harris, William (2002) Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets 13:301-6
Park, Yongsoon; Harris, William (2002) EPA, but not DHA, decreases mean platelet volume in normal subjects. Lipids 37:941-6
Park, Y; Damron, B D; Miles, J M et al. (2001) Measurement of human chylomicron triglyceride clearance with a labeled commercial lipid emulsion. Lipids 36:115-20
Park, Y; Grellner, W J; Harris, W S et al. (2000) A new method for the study of chylomicron kinetics in vivo. Am J Physiol Endocrinol Metab 279:E1258-63
Harris, W S; Hustvedt, B E; Hagen, E et al. (1997) N-3 fatty acids and chylomicron metabolism in the rat. J Lipid Res 38:503-15