ApoE is a polymorphic protein and two of the isoforms, apoE3 and E4, differ by a single amino acid with apoE4 having arginine substituted for cysteine. ApoE4 is catabolized faster than apoE3, and this is due to both the addition of a positive charge to apoE4 and, with the absence of the cysteine, the inability of apoE4 to form slowly catabolized disulfide dimers. ApoE can bind to LDL receptors and individuals with no LDL receptors have elevated levels of apoE. These elevated apoE levels are due to an increased apoE production rate with a normal catabolic rate. Individuals with apoE have increased LDL levels and this is a result of both increased production and decreased catabolism of LDL. Subjects with hypoalphalipoproteinemia with an associated restriction fragment length polymorphism of their apoA-I gene have a normal synthetic rate of a structurally and metabolically normal apoA-I with rapid catabolism of apoA-I. Therefore, the causative mutation is likely to be in a gene close to, but not in, the gene for apoA-I. Abeta and homozygous hypobetalipoproteinemia are characterized by an absence of apoB in plasma. Both types of subjects have a normal apoB gene by Southern blot analysis, and synthesize normal sized apoB mRNA. Abeta subjects have 5 times normal levels of apoB mRNA and increased amounts of apoB protein while hypobeta subjects have 10% of normal levels of apoB mRNA and decreased amounts of apoB protein in hepatocytes. The defect in abeta subjects is likely to be in the post-translational modification and secretion of apoB while the hypobeta subjects are likely to have a structurally abnormal protein that can not be secreted.
