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  Section: General Biochemistry » Lipoprotein Cholesterol Metabolism
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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.

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