Title
Apolipoprotein CI overexpression is not a relevant strategy to block cholesteryl ester transfer protein (CETP) activity in CETP transgenic mice
Author
TNO Kwaliteit van Leven
Gautier, T.
Masson, D.
Jong, M.C.
Pais De Barros, J.P.
Duverneuil, L.
Le Guern, N.
Deckert, V.
Dumont, L.
Bataille, A.
Zak, Z.
Jiang, X.C.
Havekes, L.M.
Lagrost, L.
Publication year
2005
Abstract
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·h-1·(μg 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. Chemicals / CAS: Apolipoproteins C; Apoproteins; Carrier Proteins; CETP protein, human; Cholesterol Ester Transfer Proteins; Cholesterol, 57-88-5; Glycoproteins; Lipoproteins; RNA, Messenger.
Subject
Biomedical Research
Apolipoprotein CI (apoCI)
Cholesteryl ester transfer protein (CETP)
Hyperlipidaemia
Transgenic mice
Biochemistry
Chemical activation
Esters
Genes
Reduction
Accumulation
Apolipoprotein CI (ApoCI)
High-density lipoproteins (HDL)
Mass concentration
Mice
Proteins
ABC transporter
ABC transporter G5
apolipoprotein C1
cholesterol ester transfer protein
high density lipoprotein
liver X receptor
sterol regulatory element binding protein 1c
unclassified drug
cholesterol transport
gene overexpression
lipoprotein metabolism
liver metabolism
mouse
nonhuman
priority journal
protein expression
transgenic mouse
Animals
Apolipoproteins C
Apoproteins
Carrier Proteins
Cholesterol
Cholesterol Ester Transfer Proteins
Gene Expression
Glycoproteins
Humans
Lipoproteins
Liver
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Weight
RNA, Messenger
Transgenes
Mus musculus
To reference this document use:
http://resolver.tudelft.nl/uuid:894b3abf-c1e7-40ba-a61c-f78fb6a2a088
DOI
https://doi.org/10.1042/bj20041149
TNO identifier
238293
ISSN
0264-6021
Source
Biochemical Journal, 385 (385), 189-195
Document type
article