INHIBITION OF HEPATIC CHYLOMICRON REMNANT UPTAKE BY GENE-TRANSFER OF A RECEPTOR ANTAGONIST

The low density lipoprotein receptor-related protein (LRP) has been pr oposed to mediate in concert with the LDL receptor (LDLR) the uptake o f dietary lipoproteins into the hepatocytes. This hypothesis was teste d by transient inactivation of LRP in vivo. Receptor-associated protei n (RAP), a dominant negative regulator of LRP function, was transferre d by an adenoviral vector to the livers of mice lacking LDLR (LDLR(-/- )). The inactivation of LRP by RAP was associated with a marked accumu lation of chylomicron remnants in LDLR(-/-) mice and to a lesser degre e in normal mice, suggesting that both LDLR and LRP are involved in re mnant clearance.