COMMON ISOFORMS OF APOLIPOPROTEIN E (apoE) (Lipoprotein/Cholesterol Metabolism)

Apo-E occurs in three common isoforms, apo-E2, apo-E3, and apo-E4. They differ at amino acids 112 and 158 (Table VII). In apo-E4, both of these amino acids are argi-nine. In apo-E2, both amino acids are cysteine, and apo-E3 has Cys-112 and Arg-158. The presence of cysteine at amino acid 158 virtually abolishes the LDL receptor-binding activity of apo-E. Consequently, VLDL remnants with apo-E2 accumulate in the circulation. From 0.2-1.6% of individuals in different populations are E2/E2 homozy-gotes. A subgroup of E2/E2 individuals have an unusually severe form of hypercholesterolemia due to excessive remnant lipoproteins rather than high LDL. This disorder is called Type III hyperlipidemia.

Individuals with apo-E2 exhibit delayed clearance of chylomicron remnants. The delayed clearance of remnants means cholesterol delivery to the liver is reduced. This causes an upregulation of the LDL receptor, resulting in lower plasma LDL levels. Thus, the total cholesterol in E2/E2 individuals (except those with Type III disease) might be normal, even though they have a problem clearing chylomicron remnants.

Apo-E4 is associated with higher total cholesterol levels than apo-E2 or apo-E3. This has been attributed to the relatively high affinity of apo-E4 for VLDL particles. Enrichment of VLDL with apo-E results in enhanced clearance by the liver (through the LDL receptor) and greater downregulation of the LDL receptor, thus increased LDL levels.

TABLE VII Apo-E Isoforms