Yolk is the major source of nutrients for the developing chicken embryo, but molecular details of the delivery mechanisms are largely unknown. During oogenesis in the chicken, the main yolk components vitellogenin and very low density lipoprotein (VLDL) are taken up into the oocytes via a member of the low density lipoprotein receptor gene family termed LR8 (Bujo, H., Hermann, M., Kaderli, M. O., Jacobsen, L., Sugawara, S., Nimpf, J., Yamamoto, T., and Schneider, W. J. (1994) EMBO J. 13, 5165-5175). This endocytosis is accompanied by partial degradation of the yolk precursor protein moieties; however, fragmentation does not abolish binding of VLDL to LR8. The receptor exists in two isoforms that differ by a so-called O-linked sugar domain; the shorter form (LR8؊) is the major form in oocytes, and the longer protein (LR8؉) predominates in somatic cells. Here we show that both LR8 isoforms are expressed at ratios that vary with embryonic age in the extraembryonic yolk sac, which mobilizes yolk for utilization by the embryo, and in the allantois, the embryo's catabolic sink. Stored yolk VLDL interacts with LR8 localized on the surface of the yolk sac endodermal endothelial cells (EEC), is internalized, and degraded, as demonstrated by the catabolism of fluorescently labeled VLDL in cultured EEC. Addition to the incubation medium of the 39-kDa receptor-associated protein, which inhibits all known LR8/ligand interactions, blocks the uptake of VLDL by EEC. The levels of endogenous receptor-associated protein correspond to those of LR8؉ but not LR8؊, suggesting that it may play a role in the modulation of surface presentation of LR8؉. Importantly, EEC express significant levels of microsomal triglyceride transfer protein and protein disulfide isomerase, key components required for lipoprotein synthesis. Because the apolipoprotein pattern of VLDL isolated from the yolk sac-efferent omphalomesenteric vein is very different from that of yolk VLDL, these data strongly suggest that embryo plasma VLDL is resynthesized in the EEC. LR8 is a key mediator of a two-step pathway, which affects the uptake of VLDL from the yolk sac and the subsequent delivery of its components to the growing embryo.The developing avian embryo constitutes an excellent system for the study of lipid and lipoprotein transport phenomena. The yolk, accumulated via uptake from the circulation of precursor proteins during the vitellogenic phase of oocyte growth (1), serves as the sole source of lipid, carbohydrate, and protein. Interestingly, only 350 mg of the 5-6 g of lipid in the yolk are mobilized during the first 2 weeks of embryogenesis; the major portion is transported during the final week. Such uptake, to a large part, occurs via the yolk sac (2), which utilizes the yolk lipoprotein components, following their degradation or modification, for resynthesis of lipoproteins that are subsequently secreted and delivered to the embryo through the embryonic circulatory system. The chick yolk sac is characterized by an outer layer of loosely associated mese...