Apolipoprotein E (apoE) is an important determinant for the uptake of triglyceride-rich emulsions and lipoproteins by the liver, and exerts affinity for both the LDL receptor (LDLr) and a distinct liver-specific recognition site. Our current aim was to assess the mechanism underlying the receptor-specificity of apoE-carrying lipoproteins. Triglyceride-rich emulsions were synthesized, with mean sizes of 50, 80, and 150 nm. These fractions efficiently acquired apoE from rat serum, and were processed by LPL in vivo with a similar efficiency. Upon injection of the [5H]cholesteryl oleate-labeled emulsions into rats, the liver association rate was positively correlated with particle size (24 +/- 2%, 54 +/- 1%, and 64 +/- 3% of the injected dose at 20 min after injection, respectively) and the liver uptake was predominantly exerted by parenchymal cells. The role of the LDLr in emulsion clearance was established in wild-type versus LDLr knockout mice. In the absence of the LDLr, an 8-fold increased serum half-life was observed for the small emulsion, concomitant with a 6- and 15-fold decreased uptake by the liver and adrenals at 60 min after injection, respectively. In contrast, the in vivo behavior of the large emulsion was independent of the LDLr. Both the ratio of apoE:C on the emulsions upon serum incubation and the alpha-helical content of apoE were inversely correlated with particle size, indicating that these factors may be involved in the emulsion size-dependent receptor specificity in vivo. It is concluded that the contribution of the LDLr to the apoE-mediated clearance of emulsions by the liver and adrenals strongly increases with decreasing particle size, while large particles initially associate with a distinct liver-specific recognition site. As these emulsions mimic chylomicrons, we anticipate that the apoE-dependent metabolic behavior of chylomicrons (remnants) is largely dependent on their size.