What are apoEs and what is their role in the pathophysiology of hypertriglyceridemia (high triglyceride levels)?

Updated: Jul 23, 2021
  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
  • Print

ApoEs are ligands that have greater affinity for the LDL receptor than does apo B100. In fact, the LDL receptor is more accurately designated the B/E receptor. Apo E also binds with high affinity to the LDL receptor-related protein, which takes up chylomicron remnants, VLDL, and IDL. In addition, apo E binds to cell-surface heparan sulfate proteoglycans (HSPGs), which assists in the hepatic uptake of remnant lipoproteins. [4]

The apo E gene has been cloned, sequenced, and mapped to chromosome 19. Genetically altered apo E–deficient mice develop severe dyslipidemia with accelerated atherosclerosis, whereas transgenic mice overexpressing apo E appear to be protected from atherosclerosis. [8, 9] Apo E has 3 isoforms that are present in slightly varying proportions, depending on race and geographic location. [6] Apo E3 is the most prevalent allele and for that reason was considered the “wild type” allele from which apo E2 and apo E4 were derived. Newer data, however, suggest that apoA4 was the earliest form of the protein. [10]

Most animals, including primates, possess an apo E4 equivalent. [11] Compared with apo E3, apo E2 has less affinity for the receptor, and apo E4 has more. The alleles differ in 2 amino acid positions, 112 and 158. Apo E2 is most commonly caused by cysteine substituted for arginine at position 158 in apo E3. In apo E4, an arginine is substituted for cysteine at position 112 in apo E3. The substitutions are recessive in that dysbetalipoproteinemia requires the presence of 2 apo E-2 isoforms. [11] Other very rare genetic variants of apo E exist, and several of these have been shown to have defective binding to the LDL receptor and LDL receptor-like protein. These variants act in a dominant fashion in that only 1 copy of apo E is necessary for susceptibility to development of type III hyperlipidemia.

white populations, approximately 1% of these individuals are homozygous for apo E2 (“first hit”); however, only 10% of those will develop the condition. A “second hit” is necessary, most commonly metabolic abnormalities that cause increases in VLDL. [4] Other, less common genetic conditions can also predispose people to dysbetalipoproteinemia.

More than 90% of patients with dysbetalipoproteinemia are homozygous for apo E2; the remainder have a rare, usually dominant, defect in apo E2. In addition to the apoE2 homology or defect, and combined with a metabolic condition, other genetic factors have been suggested that increase the likelihood of developing dysbetalipoproteinemia. Polymorphisms in the apo A5, lipoprotein lipase and apo C3 have all been mentioned as possible cofactors for the condition. [6]

Accumulation of IDL is caused by the poor affinity of apo E2 to LDL receptors, whereas LDL uptake via apo B100 is unaffected. In fact, total cholesterol, LDL cholesterol, and apo B are usually low compared with those with apo E3. HDL cholesterol levels may be normal or decreased. The following 3 mechanisms have been postulated for the hypocholesterolemic effect of apo E2 [12] :

  • Increased upregulation of LDL receptors due to decreased binding of lipoproteins containing apo E2

  • Increased hepatic LDL uptake due to lower LDL receptor affinity of apo E2 and consequent decreased competition with the apo B100 born by LDL (its sole apolipoprotein)

  • Apo E2 interference with lipolysis of VLDL to LDL [4]

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!