Apolipoprotein (apo) E is a 299-residue protein which functions as a key 
regulator of plasma lipid levels. Human apoE exists as three common isoforms and 
the parent form, apoE3, operates optimally in promoting clearance of 
triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid 
levels. This result occurs because apoE3 possesses both the requisite 
lipid-binding ability and affinity for the low density lipoprotein receptor 
(LDLR) to mediate appropriate lipolytic processing and endocytosis of TG-rich 
lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single 
amino acid substitution Arg158Cys located near the LDLR recognition site 
exhibits impaired binding to the receptor and an inability to promote clearance 
of TG-rich lipoprotein remnant particles; this isoform is associated with 
Type-III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single 
amino acid substitution Cys112Arg is also associated with dyslipidemia although 
binding of this isoform to the LDLR is unaffected. The amino acid substitution 
affects the organization and stability of both the N-terminal helix bundle 
domain and separately folded C-terminal domain so that apoE4 has enhanced lipid 
binding ability. As a consequence, apoE4 binds better than apoE3 to the surface 
of very low density lipoprotein (VLDL) particles and impairs their lipolytic 
processing in the circulation so that apoE4 is associated with a more 
pro-atherogenic lipoprotein-cholesterol distribution (higher 
VLDL-cholesterol/high density lipoprotein-cholesterol ratio). This review 
summarizes current understanding of the structural differences between apoE2, 
apoE3, and apoE4, and the molecular mechanisms responsible for the alterations 
in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed 
knowledge of how expression of structurally distinct apoE variants modifies 
lipoprotein metabolism provides a basis for developing ways to manipulate the 
functionality of apoE in vivo.