Apolipoprotein E2 (Lys146-->Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides.
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.
de Beer
F
F
TNO-Prevention and Health, Gaubius Laboratory, Leiden, the Netherlands.
van Dijk
K W
KW
Jong
M C
MC
van Vark
L C
LC
van der Zee
A
A
Hofker
M H
MH
Fallaux
F J
FJ
Hoeben
R C
RC
Smelt
A H
AH
Havekes
L M
LM
D000256:Adenoviridae / Q000235:genetics; D000483:Alleles; D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D006868:Hydrolysis; D006952:Hyperlipoproteinemia Type III / Q000235:genetics / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017354:Point Mutation; D012333:RNA, Messenger / Q000032:analysis; D014280:Triglycerides / Q000378:metabolism*
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014280:Triglycerides