A main strategy for lowering plasma low density lipoprotein (LDL) cholesterol levels is to increase the number of cell-surface LDL receptors (LDLRs). This can be achieved by increasing the synthesis or preventing the degradation of the LDLR. One mechanism by which an LDLR becomes non-functional， is enzymatic cleavage within the 10 residue linker region between ligand-binding repeats 4 and 5. The cleaved LDLR has only three ligand-binding repeats and is unable to bind LDL. In this study we have performed cell culture experiments to identify strategies to prevent this cleavage. As a part of these studies we found that Asp193 within the linker region is critical for cleavage to occur. Moreover， both 14-mer synthetic peptides and antibodies directed against the linker region prevented cleavage. As a consequence， more functional LDLRs were observed on the cell surface. The observation that the cleaved LDLR was present in extracts from the human adrenal gland， indicates that cleavage of the linker region takes place in vivo. Thus， preventing cleavage of the LDLR by pharmacological measures could represent a novel lipid-lowering strategy.