Diets enriched in n-6 polyunsaturated fat (Poly) compared to saturated (Satd) fat decrease the concentration of LpA-I (apoA-I only HDL [high density lipoprotein] particles) with little change in LpA-I/A-II (particles with both apoA-I and A-II). LpA-I concentrations are inversely correlated with coronary heart disease in humans. The goal of this project is to elucidate the basic mechanisms by which dietary fat saturation affects metabolism of HDL subfractions. Our preliminary studies have shown a unidirectional conversion of small LpA-I (2 apoA-I per HDL) to medium (3 apoA-I per HDL) and large LpA-I (4 apoA-I per HDL) in vivo in African green monkeys, and that animals with low HDL have one fourth the conversion rate of small to large LpA-I compared to those with high HDL concentrations. We hypothesize that diets rich in Poly compared to those containing Satd fat lead to decreased production of small LpA-I and/or to decreased conversion of the small LpA-I to medium and large LpA-I. The decreased production of small LpA-I in animals fed Poly diets may result from decreased hepatic production of LpA-I and the poor assembly of apoA-I with lipid due to decreased stability of apoA-I on Poly LpA-I particles, leading to hypercatabolism of lipid-free or lipid-poor apoA-I. An alternative hypothesis is that Poly-rich diets may result in a faster catabolism of LpA-I from plasma. Studies are designed to elucidate the mechanisms by which Poly-enriched diets result in lower plasma HDL and apoA-I concentrations, and in a decreased ratio of large to small LpA-I HDL subfractions in plasma. The following specific aims are proposed: 1) To determine the in vivo production, interconversion, and catabolism of small, medium and large spherical LpA-I in plasma of African green monkeys consuming Satd vs. Poly diets, 2) To determine whether small, medium, and large nascent discoidal LpA-I isolated from liver perfusate of monkeys are direct precursors in plasma of small, medium, and large spherical LpA-I, respectively, and whether animals fed Poly have decreased production of liver perfusate LpA-I and less conversion of liver perfusate LpA-I to plasma LpA-I in vivo, and 3) To determine the tissue sites responsible for the catabolism of medium and large LpA-I and whether selective uptake of cholesteryl ethers compared to apoA-I by perfused livers of African green monkeys fed Poly vs. Satd diets may alter particle size distribution. The results from this study will increase our basic understanding of HDL subfraction metabolism and fill gaps in knowledge of the effects of dietary fat saturation on HDL subfraction metabolism.

R01HL062411

1999-06-01

1999-06-30