Relative roles of LDLr and LRP in the metabolism of chylomicron remnants in genetically manipulated mice

Remnant-like emulsions labeled with cholesteryl [C-13]-oleate were prepared with lipid compositions similar to remnants derived from triacylglycerol-r ich lipoproteins. When injected into the bloodstream of conscious mice, the remnant-like emulsions were metabolized in the liver leading to the appear ance of (CO2)-C-13 in the breath, Previously, using this technique, we foun d that remnant metabolism was significantly impaired but not completely inh ibited in mice lacking low density lipoprotein receptors (LDLr), We have no w found in mice with non-functional low density lipoprotein receptor-relate d protein (LRP) that breath enrichment of (CO2)-C-13 was significantly decr eased, indicating that the LRP also plays an important role in the metaboli sm of chylomicron remnants (CR), The enrichment of (CO2)-C-13 in the expire d breath was negligible in mice lacking both LDLr and receptor-associated p rotein (-/-), essential for normal function of LRP. In mice pre-injected wi th gluthatione S-transferase-receptor-associated protein to block LRP bindi ng, there was a marked inhibition of the appearance of (CO2)-C-13 in the ex pired breath of homozygous LDLr-deficient mice, supporting the role of LRP in vivo, Whether or not LDLr were present, in mouse and human fibroblast ce lls human apoE3 or E4 but not apoE2 were essential for binding of remnant-l ike emulsions, while lactoferrin and suramin completely inhibited binding. We conclude that in normal mice LDLr are important for the physiological me tabolism of CR. When LDLr are absent the evidence supports a role for the L RP in the uptake of CR in liver cells and in fibroblasts, with binding char acteristics for CR-associated apoE similar to LDLr.