Apolipoprotein CI overexpression is not a relevant strategy to block cholesteryl ester transfer protein (CETP) activity in CETP transgenic mice.
ApoCI (apolipoprotein CI) is a potent inhibitor of plasma CETP [CE (cholesteryl ester) transfer protein]. The relevance of apoCI overexpression as a method for CETP blockade in vivo was addressed in the present study in CETPTg/apoCITg mice (mice expressing both human CETP and apoCI). Despite a significant reduction in specific CETP activity in CETPTg/apoCITg mice compared with CETPTg mice [transgenic mouse to human CETP; 46.8+/-11.1 versus 101.8+/-25.7 pmol x h(-1).(mug of plasma CETP)(-1) respectively; P<0.05], apoCI overexpression increased both the CETP mass concentration (3-fold increase; P<0.05) and the hepatic CETP mRNA level (4-fold increase, P<0.005), leading to an increase in total plasma CE transfer activity (by 39%, P<0.05). The ratio of apoB-containing lipoprotein to HDL (high-density lipoprotein) CE was 10-fold higher in CETPTg/apoCITg mice than in apoCITg mice (P<0.0005). It is proposed that the increased CETP expression in CETPTg/apoCITg mice is a direct consequence of liver X receptor activation in response to the accumulation of cholesterol-rich apoB-containing lipoproteins. In support of the latter view, hepatic mRNA levels of other liver X receptor-responsive genes [ABCG5 (ATP-binding cassette transporter GS) and SREBP-1c (sterol-regulatory-binding protein-1c)] were higher in CETPTg/apoCITg mice compared with CETPTg mice. In conclusion, overexpression of apoCI, while producing a significant inhibitory effect on specific CETP activity, does not represent a suitable method for decreasing total CE transfer activity in CETPTg/apoCITg mice, owing to an hyperlipidaemia-mediated effect on CETP gene expression.
Gautier
Thomas
T
Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France.
Masson
David
D
Jong
Miek C
MC
Pais de Barros
Jean-Paul
JP
Duverneuil
Linda
L
Le Guern
Naig
N
Deckert
Valérie
V
Dumont
Laure
L
Bataille
Amandine
A
Zak
Zoulika
Z
Jiang
Xian-Cheng
XC
Havekes
Louis M
LM
Lagrost
Laurent
L
D000818:Animals; D001056:Apolipoproteins C / Q000235:genetics* / Q000378:metabolism*; D001059:Apoproteins / Q000097:blood; D002352:Carrier Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D015870:Gene Expression; D006023:Glycoproteins / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000097:blood* / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008970:Molecular Weight; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D019076:Transgenes / Q000235:genetics*
D001056:Apolipoproteins C; D001059:Apoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008074:Lipoproteins; D012333:RNA, Messenger; D002784:Cholesterol