This research is a continuing investigation of the kinetics of apolipoprotein metabolism in humans. Apolipoproteins are plasma mediators of lipid transport, and this investigation concerns the relationship between plasma lipid transport and the secretion of apolipoproteins into plasma. Two general hypotheses underlie our studies. 1) We proposed that the matabolism of the individual apolipoproteins is coordinated and that the system functions in response to the requirements for plasma transport of individual lipids. Accordingly we shall measure the plasma secretory rates for the major apolipoproteins and for triglyceride, cholesterol, its esters and phospholipid, using biosynthetically incorporated tracers of H3-leucine, H3-mevalonate and C14-glycerol. Normal subjects and those with selected hyperlipoproteinemias will be studied on a common diet and again after metabolic perturbation, by cholesterol feeding, an Omega-3 fatty acid enriched fat diet, administration of cholestyramine or Mevinolin. The secretory rate constants and plasma transports measured for apoproteins and individual lipids will be compared under these various conditions, chosen to provide insight into control mechanisms regulating apolipoprotein metabolism. 2) We will examine the pathways for secretion of apo B containing lipoproteins to document relationships between secretory routes and physical heterogencity of these lipoproteins. We propose that physical heterogeneity within the apo B containing lipoproteins results from apo B secretion along pathways entering different lipoprotein species and that the magnitude of apo B transport over individual secretory pathways is determined by the amount of lipid to be transported by this apolipoprotein. This hypothesis will be examined in the same subjects, measuring plasma lipid transport rates and apo B secretion into VLDL, IDL and the fractionated LDL subspecies. These studies will thus initiate an investigation of the relationship between apolipoprotein production and the quantity of lipid being transported in plasma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029394-05
Application #
3340490
Study Section
Metabolism Study Section (MET)
Project Start
1982-09-01
Project End
1990-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Fisher, W R; Venkatakrishnan, V; Fisher, E S et al. (1997) The 3H-leucine tracer: its use in kinetic studies of plasma lipoproteins. Metabolism 46:333-42
Venkatakrishnan, V; Fisher, W R; Zech, L A (1997) Determination of the radiation dose from administered apolipoprotein tracers in humans. Metabolism 46:1231-9
Fisher, W R; Venkatakrishnan, V; Zech, L A et al. (1995) Kinetic evidence for both a fast and a slow secretory pathway for apolipoprotein A-I in humans. J Lipid Res 36:1618-28
Fisher, W R; Zech, L A; Stacpoole, P W (1994) ApoB metabolism in familial hypercholesterolemia. Inconsistencies with the LDL receptor paradigm. Arterioscler Thromb 14:501-10
Stacpoole, P W; von Bergmann, K; Kilgore, L L et al. (1991) Nutritional regulation of cholesterol synthesis and apolipoprotein B kinetics: studies in patients with familial hypercholesterolemia and normal subjects treated with a high carbohydrate, low fat diet. J Lipid Res 32:1837-48
Fisher, W R; Zech, L A; Kilgore, L L et al. (1991) Metabolic pathways of apolipoprotein B in heterozygous familial hypercholesterolemia: studies with a [3H]leucine tracer. J Lipid Res 32:1823-36
Beltz, W F; Kesaniemi, Y A; Miller, N H et al. (1990) Studies on the metabolism of apolipoprotein B in hypertriglyceridemic subjects using simultaneous administration of tritiated leucine and radioiodinated very low density lipoprotein. J Lipid Res 31:361-74
Stacpoole, P W; Alig, J; Kilgore, L L et al. (1988) Lipodystrophic diabetes mellitus. Investigations of lipoprotein metabolism and the effects of omega-3 fatty acid administration in two patients. Metabolism 37:944-51
Patterson, B W; Hansard 2nd, S L; Ammerman, C B et al. (1986) Kinetic model of whole-body vanadium metabolism: studies in sheep. Am J Physiol 251:R325-32
Patterson, B W; Lee, A M (1986) Self-association and phospholipid binding properties of iodinated apolipoprotein A-I. Biochemistry 25:4953-7

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