Common Isoforms of Apolipoprotein E (Apoe)
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 arginine. 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 receptorbinding 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 homozygotes. 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
Apo-E2 | Apo-E3 | Apo-E4 | |
---|---|---|---|
Amino acid 112 | Cys | Cys | Arg |
Amino acid 158 | Cys | Arg | Arg |
LDL receptor binding | <0.1% | Normal | Normal |
LDL cholesterol | Low | Normal | High |
VLDL cholesterol | High | Normal | Normal |
TABLE VIII Major Lipoprotein Disorders
Disorder | Principal plasma abnormality | Clinical features a | Estimated frequency |
---|---|---|---|
Heterozygous familial hypercholesterolemia | ↑LDL | Tendinous xanthomas, cornial arcus, premature CAD; family history of hypercholesterolemia | 0.2% of general population; 5% of MI survivors under age 60 |
Familial combined hyperlipidemia | ↑1/3 LDL only, ↑1/3 VLDL only, ↑1/3 LDL & VLDL, apoB overproduction common | Patients usually over age 30, often overweight, usually no xanthomas or premature CAD | 0.5% of general population; 15% of MI survivors under age 60 |
Polygenic hypercholesterolemia | ↑LDL | Premature CAD, no xanthomas | Unknown |
Familial hypertriglyceridemia (200–500 mg/dl) | ↑VLDL only | Patients often overweight, usually do not have xanthomas or premature CAD | 1% of general population; 5% of MI survivors under age 60 |
Severe hypertriglyceridemia (>1000 mg/dl) | ↑Chylomicrons & ↑VLDL | Patients usually middle age, obese, hyperuricemic, diabetic, at risk for pancreatitis | Unknown |
Familial hypoalphalipoproteinemia | ↓HDL | Premature CAD | ∼40% of patients with premature CAD |
aCAD, Coronary artery disease; MI, myocardial infarction. |