Dietary fish oil decreases low-density-lipoprotein clearance in nonhuman primates

To assess whether fish oil-induced alterations in low-density-lipoprotein (LDL) composition have distinct and important effects on LDL metabolism, we evaluated LDL kinetic behavior in cynomolgus macaques fed an atherogenic diet supplemented with either fish oil (1.6 g n-3 fatty acids; n = 10) or olive oil (n = 9) for > or = 6 mo. LDL from monkeys supplemented with fish oil or olive oil was isolated, labeled with either 125I or 131I, and simultaneously reinjected so that each monkey received its own (autologous injection) and donor (homologous injection) LDL. For LDL injected autologously (monkeys that received their own LDL), the LDL fractional clearance rate (FCR) was reduced in fish oil-supplemented monkeys compared with the olive oil-supplemented controls (0.42 +/- 0.03 compared with 0.56 +/- 0.05 pools/d, P = 0.04). The cholesteryl ester content of fish oil LDL increased compared with olive oil LDL (43 +/- 2% and 36 +/- 3%, respectively, P = 0.03), and the LDL cholesteryl ester content was strongly correlated with autologous LDL clearance (r = -0.76, P = 0.0001). Compared with olive oil LDL, fish oil LDL had a reduced dissociation constant (KD) for binding to the LDL receptor in vitro (KD for fish oil LDL compared with olive oil LDL: 13.9 +/- 1.8 and 7.4 +/- 1.0 mg LDL protein/L, P = 0.03). When both fish oil LDL and olive oil LDL were simultaneously injected into fish oil-supplemented monkeys, the FCR of fish oil LDL was decreased compared with olive oil LDL (0.42 +/- 0.03 and 0.52 +/- 0.04 pools/d, P = 0.006). These data suggest that dietary supplementation with fish oil decreases LDL clearance, and that this effect is mediated, at least in part, by altering LDL structure and reducing the affinity of LDL for its receptor.