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.
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