Abstract-Type III hyperlipoproteinemia (HLP) is mainly found in homozygous carriers of apolipoprotein E2 (apoE2, Arg1583 Cys). Only a small percentage (Ͻ5%) of these apoE2 homozygotes develops hyperlipidemia, indicating that additional environmental and genetic factors contribute to the expression of type III HLP. In the present study, first, the prevalence of type III HLP among apoE2 homozygotes was estimated in a Dutch population sample of 8888 participants. Second, 68 normocholesterolemic and 162 hypercholesterolemic apoE2 homozygotes (type III HLP patients) were collected to investigate additional factors influencing type III HLP expression. In the Dutch population sample, apoE2 homozygosity occurred with a frequency of 0.6% (57 of 8888 individuals). Among the 57 E2/2 subjects, 10 type III HLP patients were identified (prevalence 18%). Comparison of normocholesterolemic E2/2 subjects and type III HLP patients showed that the latter had a significantly increased body mass index (25.6Ϯ4.0 versus 26.9Ϯ3.8 kg/m 2 , respectively; Pϭ0.03) and prevalence of hyperinsulinemia (26% versus 63%, respectively; PϽ0.001). Multiple linear regression analysis demonstrated that most of the variability in type III HLP expression can be explained by fasting insulin levels (partial correlation coefficient Ϸ0.50, PϽ0.001). In contrast to men, apoE2 homozygous women aged Ն50 years had significantly higher plasma lipid levels than their counterparts aged Ͻ50 years. These data demonstrate that the expression of type III HLP in E2/2 subjects is elicited to a large extent by hyperinsulinemia. In addition, in female apoE2 homozygotes, the expression increases with age; this increase is most likely due to the loss of estrogen production. Key Words: type III hyperlipoproteinemia Ⅲ apolipoprotein E Ⅲ hyperinsulinemia F amilial dysbetalipoproteinemia (FD) is an inborn error of metabolism characterized by defective apoE, leading to the impaired clearance of remnant lipoproteins by the liver. 1,2 FD subjects are characterized by an accumulation of chylomicron and VLDL remnants in the circulation. These socalled ␤-VLDL particles are enriched in cholesterol esters and apoE. 3,4 ApoE is a ligand for the receptor-mediated uptake of chylomicron and VLDL remnants by the liver. 5-7 Three alleles encode for 3 apoE isoforms: apoE2 (Arg1583 Cys), apoE3 (Cys112, Arg158), and apoE4 (Cys1123 Arg). 8 In contrast to the other 2 common apoE isoforms, apoE2 displays Ͻ1% binding affinity for the hepatic LDL receptor (LDLR). 9,10 More than 90% of all FD subjects are homozygous carriers of apoE2 (Arg1583 Cys). 1,11 In white populations, apoE2 homozygosity occurs with a frequency of Ϸ1%. 2 Despite the accumulation of remnants in the circulation, most (Ͼ95%) apoE2 homozygous subjects are normolipidemic or even hypolipidemic because of low LDL cholesterol levels. 11-13 However, apoE2 homozygosity together with the presence of additional environmental and/or genetic factors that interfere with normal lipoprotein metabolism will often result in a hyperlipidemic phen...

In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.

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The apolipoprotein E2 (Lys146-->Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL) fraction are due to a disturbed lipolysis of VLDL. To test this hypothesis, apoE knockout mice were injected with an adenovirus containing the human APOE*2 (Lys146-->Gln) gene, Ad-E2(146), under the control of the cytomegalovirus promoter. ApoE knockout mice injected with an adenovirus vector encoding human apoE3 (Ad-E3) were used as controls. Five days after adenovirus injection, plasma cholesterol levels of mice injected with a high dose of Ad-E2(146) (2x10(9) plaque-forming units) were not changed compared with preinjection levels, whereas in the group who received a low dose of Ad-E2(146) (5x10(8) plaque-forming units) and in the groups injected with a low or a high dose of Ad-E3, plasma cholesterol levels were decreased 5-, 6-, and 12-fold, respectively. Plasma triglycerides were not affected in mice injected with Ad-E3. In contrast, a 7-fold increase in plasma triglycerides was observed in mice injected with the low dose of Ad-E2(146) compared with mice injected with Ad-E3. Injection with the high dose of Ad-E2(146) resulted in a dramatic increase of plasma triglycerides (50-fold compared with Ad-E3 injection). In vitro lipolysis experiments showed that the lipolysis rate of VLDLs containing normal amounts of apoE2 (Lys146-->Gln) was decreased by 54% compared with that of VLDLs containing comparable amounts of apoE3. The in vivo VLDL-triglyceride production rate of Ad-E2(146)-injected mice was not significantly different from that of Ad-E3-injected mice. These results demonstrate that expression of apoE2 (Lys146-->Gln) causes hypertriglyceridemia due to an apoE variant-specific inhibition of the hydrolysis of VLDL-triglycerides.