Apolipoprotein E2 (Lys146→Gln) Causes Hypertriglyceridemia due to an Apolipoprotein E Variant–Specific Inhibition of Lipolysis of Very Low Density Lipoproteins–Triglycerides

Abstract

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.

Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study

“…Thus, carriers of the *e2 allele (which has a dramatically reduced affinity for binding) are less efficient at making and transferring VLDLs and chylomicrons from the blood to the liver and thus are slower to take up postprandial lipoprotein particles compared with *e3 and *e4 carriers. These APOE genetic variants have been associated with LDL variation across multiple populations (12,13) as well as with other lipid-related traits, such as triglyceride concentration (46). In addition, interactions between the APOE polymorphisms and environmental modulators, such as nutrient intake (14,47), sex (48), age (49), smoking behavior (49), alcohol consumption (50), and type 2 diabetes (49), have all been indicated.…”

Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion

“…39,40 These isoforms differ only in a single amino acid from APOE3. Because APOE3Leiden is not able to increase VLDL-TG secretion, our results indicate that incorrect folding of the APOE molecule caused by the introduction of a tandem repeat of 7 amino acids is associated with impaired VLDL secretion.…”

Quantitative Trait Linkage Analysis of Lipid-Related Traits in Familial Type 2 Diabetes

“…Interaction of rare ApoC2 variants and the ApoE4 allele has also been described (51). Finally, the ApoE2 allele also may cause hypertriglyceridemia (52). The roles of the ApoC1 and ApoC4 genes are uncertain, but variation is a plausible cause of hypertriglyceridemia.…”