Apolipoprotein E2 (Lys146 -> Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low densitylipoproteins-triglycerides

The apolipoprotein E2 (Lys146-->Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this vari ant have elevated levels of plasma triglycerides, cholesterol, and apolipop rotein 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 inject ed with an adenovirus containing the human APOE*2 (Lys146-->Gln) gene, Ad-E 2(146), under the control of the cytomegalovirus promoter. ApoE knockout mi ce injected with an adenovirus vector encoding human apoE3 (Ad-E3) were use d as controls. Five days after adenovirus injection, plasma cholesterol lev els of mice injected with a high dose of Ad-E2(146) (2 x 10(9) plaque-formi ng units) were not changed compared with preinjection levels, whereas in th e group who received a low dose of Ad-E2(146) (5 x 10(8) plaque-forming uni ts) and in the groups injected with a low or a high dose of Ad-E3, plasma c holesterol 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, Injecti on with the high dose of Ad-E2(146) resulted in a dramatic increase of plas ma triglycerides (50-fold compared with Ad-E3 injection). In vitro lipolysi s experiments showed that the lipolysis rate of VLDLs containing normal amo unts of apoE2 (Lys146-->Gln) was decreased by 54% compared with that of VLD Ls containing comparable amounts of apoE3. The in vivo VLDL-triglyceride pr oduction rate of Ad-E2(146)-injected mice was not significantly different f rom 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.