ApoE and lipoprotein metabolism

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ApoE is a key apoprotein involved in triglyceride-rich lipoprotein (IDL and chylomicron remnants) uptake by the liver and peripheral tissues through interaction with apoB,E and remnant receptors. Two common variations exist through C to T transition, leading to variations in the amino acids p.Cysll2Arg* and p.Argl58Cys. This results in three major alleles (E2, E3, E4) with relative frequencies ofO.l, 0.8 and0.l5, respectively. The apoE-E2 allelic product binds poorly to the remnant receptor, leading to accumulation of triglyceride-rich lipoproteins in the circulation. Conversely, the apoE-E4 allelic product has high affinity and increases TRL uptake by the liver, thus inducing a down-regulation of the apoB,E receptor level, reduced LDL uptake and increased LDL accumulation (Sing and Davignon, l985). It is noteworthy that such apoE polymorphisms account for about 8-l0% of total plasma cholesterol-rich variation (Schaefer et al., l994).

Several studies have investigated the relationship between apoE polymorphisms and responses to diets. Healthy men ingesting a low-fat diet vs their usual high-fat, cholesterol diet showed extents of reduction in LDL cholesterol in the following order E4/E4 = E4/E3 > E3/E3 > E3/E2 (Dreon et al., l995). In a cohort of men and women with coronary heart disease, a high sucrose intake resulted in higher plasma triglyceride concentration only in patients with the apoE-E2 allele. In these patients too, saturated fat or fibre intake predicted serum cholesterol levels (Erkkila et al., 200l). The response to a fat-rich test-meal was also investigated in normolipidaemic patients with type 2 diabetes (Reznik et al., l996). In this study the accumulation of TRL remnants (retinyl palmitate) was postprandially exacerbated in patients with E2/E3 or E3/E4 genotypes. Finally, the response to alcohol drinking was evaluated in a cohort of healthy men and women (Corella et al., 200l). In this study men and women with the apoE-E2 allele had lower LDL cholesterol levels, while men with the E4 allele had the highest LDL cholesterol levels. We have also investigated the influence of the combination of apoE-E2 and a rare apoE-E3 'Christchurch' mutant p.Argl36Ser (Vialettes et al., 2000). This genotype was associated with type V hyperlipoproteinaemia and it exacerbated postprandial lipaemia and TRL-remnant accumulation. Taken together, information available on apoE polymorphisms clearly indicate that apoE-E2 or E4 variants are associated with disturbed lipid metabolism and altered lipoprotein response to dietary challenge.

* Genetic variations are described according to the recommendations of the Human Genome Variation Society (http://www.genomic.unimelb.edu.au/mbi/dblist/dblist.html).

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