ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoA-V but unaffected by apoC-III deficiency.
Apolipoprotein E2 (apoE2)-associated hyperlipidemia is characterized by a disturbed clearance of apoE2-enriched VLDL remnants. Because excess apoE2 inhibits LPL-mediated triglyceride (TG) hydrolysis in vitro, we investigated whether direct or indirect stimulation of LPL activity in vivo reduces the apoE2-associated hypertriglyceridemia. Here, we studied the role of LPL and two potent modifiers, the LPL inhibitor apoC-III and the LPL activator apoA-V, in APOE2-knockin (APOE2) mice. Injection of heparin in APOE2 mice reduced plasma TG by 53% and plasma total cholesterol (TC) by 18%. Adenovirus-mediated overexpression of LPL reduced plasma TG by 85% and TC by 40%. Both experiments indicate that the TG in apoE2-enriched particles is a suitable substrate for LPL. Indirect activation of LPL activity via deletion of Apoc3 in APOE2 mice did not affect plasma TG levels, whereas overexpression of Apoa5 in APOE2 mice did reduce plasma TG by 81% and plasma TC by 41%. In conclusion, the hypertriglyceridemia in APOE2 mice can be ameliorated by the direct activation of LPL activity. Indirect activation of LPL via overexpression of apoA-V does, whereas deletion of apoC-III does not, affect the plasma TGs in APOE2 mice. These data indicate that changes in apoA-V levels have a dominant effect over changes in apoC-III levels in the improvement of APOE2-associated hypertriglyceridemia.
Gerritsen
Gery
G
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
van der Hoogt
Caroline C
CC
Schaap
Frank G
FG
Voshol
Peter J
PJ
Kypreos
Kyriakos E
KE
Maeda
Nobuyo
N
Groen
Albert K
AK
Havekes
Louis M
LM
Rensen
Patrick C N
PC
van Dijk
Ko Willems
KW
D000256:Adenoviridae; D000818:Animals; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000494:pharmacology*; D053329:Apolipoprotein E2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001053:Apolipoproteins / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D015228:Hypertriglyceridemia / Q000097:blood*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout
C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D053329:Apolipoprotein E2; D001053:Apolipoproteins; D008055:Lipids; D008071:Lipoprotein Lipase