Apolipoprotein CI overexpression is not a relevant strategy to block cholesteryl ester transfer protein (CETP) activity in CETP transgenic mice
article
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.
Topics
Biomedical ResearchApolipoprotein CI (apoCI)Cholesteryl ester transfer protein (CETP)HyperlipidaemiaTransgenic miceBiochemistryChemical activationEstersGenesReductionAccumulationApolipoprotein CI (ApoCI)High-density lipoproteins (HDL)Mass concentrationMiceProteinsABC transporterABC transporter G5apolipoprotein C1cholesterol ester transfer proteinhigh density lipoproteinliver X receptorsterol regulatory element binding protein 1cunclassified drugcholesterol transportgene overexpressionlipoprotein metabolismliver metabolismmousenonhumanpriority journalprotein expressiontransgenic mouseAnimalsApolipoproteins CApoproteinsCarrier ProteinsCholesterolCholesterol Ester Transfer ProteinsGene ExpressionGlycoproteinsHumansLipoproteinsLiverMiceMice, Inbred C57BLMice, TransgenicMolecular WeightRNA, MessengerTransgenesMus musculus
TNO Identifier
238293
ISSN
0264-6021
Source
Biochemical Journal, 385(1), pp. 189-195.
Pages
189-195
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