Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice.
We have recently shown that the predominant hypertriglyceridemia in human apolipoprotein C1 (APOC1) transgenic mice is mainly explained by apoCI-mediated inhibition of the lipoprotein lipase (LPL)-dependent triglyceride (TG)-hydrolysis pathway. Since the very-low-density lipoprotein receptor (VLDLr) and apoCIII are potent modifiers of LPL activity, our current aim was to study whether the lipolysis-inhibiting action of apoCI would be dependent on the presence of the VLDLr and apoCIII in vivo. Hereto, we employed liver-specific expression of human apoCI by using a novel recombinant adenovirus (AdAPOC1). In wild-type mice, moderate apoCI expression leading to plasma human apoCI levels of 12-33 mg/dl dose-dependently and specifically increased plasma TG (up to 6.6-fold, P < 0.001), yielding the same hypertriglyceridemic phenotype as observed in human APOC1 transgenic mice. AdAPOC1 still increased plasma TG in vldlr(-/-) mice (4.1-fold, P < 0.001) and in apoc3(-/-) mice (6.8-fold, P < 0.001) that were also deficient for the low-density lipoprotein receptor (LDLr) and LDLr-related protein (LRP) or apoE, respectively. Thus, irrespective of receptor-mediated remnant clearance by the liver, liver-specific expression of human apoCI causes hypertriglyceridemia in the absence of the VLDLr and apoCIII. We conclude that apoCI is a powerful and direct inhibitor of LPL activity independent of the VLDLr and apoCIII.
van der Hoogt
Caroline C
CC
The Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands. C.C.van_der_Hoogt@lumc.nl
Berbée
Jimmy F P
JF
Espirito Santo
Sonia M S
SM
Gerritsen
Gery
G
Krom
Yvonne D
YD
van der Zee
André
A
Havekes
Louis M
LM
van Dijk
Ko Willems
KW
Rensen
Patrick C N
PC
D000818:Animals; D053302:Apolipoprotein C-I; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001483:Base Sequence; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D053302:Apolipoprotein C-I; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D026502:LDL-Receptor Related Proteins; D008055:Lipids; D012333:RNA, Messenger; D011973:Receptors, LDL; D011994:Recombinant Proteins; C036053:VLDL receptor; D008071:Lipoprotein Lipase