Effect of CETP on the Plasma Lipoprotein Profile in Four Strains of Transgenic Mouse

Takahashi, Hikaru; Takahashi, Akiko; Maki, Mimi; Sasai, Hisanori; Kamada, Masafumi

doi:10.1006/bbrc.2001.4743

Cited by 12 publications

(10 citation statements)

References 25 publications

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“…In contrast to wild-type mice, treatment of CETPTg mice with T0901317 produced no significant alterations in the plasma lipid concentrations, indicating in this case that the known ABCA1-and PLTP-mediated rises in plasma HDL cholesterol are compensated for by another mechanism involving CETP. Indeed, CETP is recognized as a key factor in promoting in vivo the net transfer of CEs from HDL-to apoB-containing lipoproteins (19,22,23). In the present study, the appearance of large-sized HDL1 upon LXR activation in wild-type mice was completely abolished in CETPTg mice, again supporting the peculiar sensitivity of this HDL subpopulation to CETP-mediated remodeling (12,32,35).…”

Section: Discussionmentioning

confidence: 99%

“…Through its action, CETP is likely to influence both the atherogenicity of the lipoprotein profile and the centripetal flux of cholesterol from peripheral tissues toward the liver, a process also called reverse cholesterol transport. In particular, the rise in plasma CETP level in CETP transgenic mice is associated with the redistribution of CEs from the antiatherogenic HDLs to the proatherogenic VLDLs and LDLs (19)(20)(21)(22)(23). The lack of active CETP in the mouse may be a major limitation to the study of cholesterol homeostasis after LXR agonist administration, because CETP, one key factor in RCT, is a wellknown LXR target (24,25).…”

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confidence: 99%

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Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse

Masson

Staels

Gautier

et al. 2004

Journal of Lipid Research

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Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of Recently, the use of synthetic liver X receptor (LXR) agonists appeared as a potential new pharmacological approach to stimulating reverse cholesterol transport (RCT) in vivo (1, 2). LXRs ␣ and ␤ are nuclear receptors that are activated by oxysterols (3, 4). They are involved in the regulation of cholesterol homeostasis, lipogenesis, glucose metabolism, and inflammation (4-9). Moreover, LXR agonist administration inhibits the development of atherosclerosis in LDL receptor (LDLR)-deficient and apolipoprotein E (apoE)-deficient mouse models, an effect that probably results from the modulation of the expression of both metabolic and inflammatory genes (10, 11). With regard to cholesterol metabolism, LXRs regulate RCT by inducing the expression of genes that are involved in cellular efflux, plasma transport, and biliary excretion of cholesterol. In animal models, the activation of LXR by synthetic agonists was shown to increase plasma HDL concentration, probably as the result of the induction of phospholipid transfer protein (PLTP), and ATP binding cassette (ABC) transporters A1 and G1 (12-14). LXR activation is also associated with a decrease in cholesterol content of the liver, an increase in biliary cholesterol secretion, and an increase in fecal neutral sterol excretion (5,15,16). Expression of the transporters ABCG5/G8 is known to be required for the latter phenomena to occur (15).It is worth noting that most of the previous studies with LXR agonists were conducted in the mouse, an animal model having no plasma cholesteryl ester transfer protein (CETP) activity (17). CETP is a plasma glycoprotein that promotes the exchange of neutral lipids, i.e., cholesteryl Abbreviations: CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; LXR, liver X receptor; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SREBP, sterol-responsive element binding protein.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse

Masson

Staels

Gautier

et al. 2004

Journal of Lipid Research

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“…Thus, the expected phenotypes of increased HDL levels in mice overexpressing apo AI and LCAT and decreased HDL levels in mice expressing CETP were not observed after 4 months on the atherogenic diet. Previous studies (25)(26)(27) have shown that the HDL-lowering effect of CETP expression is not observed after treatment with this atherogenic diet or in endogenous hypercholesterolemia resulting from LDL receptor gene knockout.…”

Section: Discussionmentioning

confidence: 95%

Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

Berti

Faria

Oliveira

2005

Braz J Med Biol Res

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We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/ CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R 2 ) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R 2 = 0.22, P < 0.001) and CETP (R 2 = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R 2 = 0.16, P < 0.005) and LCAT/AI (R 2 = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific atherogenic scenarios.

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“…4,23 The human CETP transgenic mice (C57BL/6) were gifts from Japan Tobacco Inc (Tokyo). 24,25 The homozygous LCAT-deficient mice were cross-bred with the highly expressing CETP transgenic mice to produce the F1 mice, and the F2 mice were derived from a total of 15 matings between the F1 mice. The F2 mice were weaned at 3 weeks (nϭ63, 32 males and 31 females).…”

Section: Animalsmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Expressed in Lecithin Cholesterol Acyltransferase–Deficient Mice

Tsujita²,

Okumura-Noji³

et al. 2002

ATVB

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Objective-Regulation of plasma cholesteryl ester transfer protein (CETP) concentration was studied in lecithin-cholesterol acyltransferase (LCAT)-knockout mice. Methods and Results-LCAT-knockout mice were cross-bred with CETP transgenic mice. The offspring (nϭ63) were classified for LCAT genotype and plasma CETP levels (no CETP, low CETP, and high CETP). High density lipoprotein (HDL) decreased as LCAT decreased in each CETP-level group. In the lcat(ϩ/ϩ) and lcat(ϩ/Ϫ) mice, plasma CETP varied from 0 to 30 g/mL, whereas it was Ͻ10 g/mL in the lcat(Ϫ/Ϫ) mice. HDL cholesterol and phospholipid decreased and HDL triglyceride and apolipoprotein B increased in CETP in the lcat(ϩ/ϩ) and lcat(ϩ/Ϫ) mice, whereas there was no difference in HDL between low and high CETP. An effect of CETP on HDL was not detected in the lcat(Ϫ/Ϫ) mice because of the absence of mature HDL. Genomic DNA and mRNA of CETP were correlated and were similar in the lcat(Ϫ/Ϫ) and lcat(ϩ/ϩ) mice. Plasma CETP was correlated with its genomic DNA and mRNA, but the slope of the increase was much lower in the lcat(Ϫ/Ϫ) mice. Whereas plasma CETP mostly associates with HDL in the lcat(ϩ/ϩ) mouse, it is found free in the lcat(Ϫ/Ϫ) mouse. Key Words: cholesterol Ⅲ high density lipoprotein Ⅲ lecithin-cholesterol acyltransferase Ⅲ cholesteryl ester transfer protein Ⅲ mice H igh density lipoprotein (HDL) is given a key role in the hypothesis of a cholesterol transport pathway from the peripheral tissues to the liver. Lecithin-cholesterol acyltransferase (LCAT) plays a major role in this process by esterifying free cholesterol (FC) in circulating lipoproteins to maintain a FC gradient between the peripheral cells and the HDL particle surface and, accordingly, to promote FC efflux from the cells. 1 The importance of LCAT in HDL metabolism has been established by identification and characterization of the patients with LCAT deficiency. 2 Mutations in the human LCAT gene cause either familial LCAT deficiency or fish eye disease, which results in the decrease of plasma HDL and accumulation of cholesterol in the cell membrane in certain organs. 2 Disruption of the LCAT gene in mice also exhibits severe reduction of plasma HDL 3,4 and mimics many features of LCAT deficiency in humans. Conclusions-PlasmaThe cholesteryl ester (CE) generated by LCAT and present in the HDL core can be transported directly to the liver by selective uptake 5,6 and/or potentially as a whole particle. 7 Alternatively, HDL CE is transferred to apoB-containing lipoproteins by CE transfer protein (CETP) for liver uptake. 8 CETP is a plasma glycoprotein that mediates transfer/exchange of CE and triglycerides between HDL and apoBcontaining lipoproteins. 9,10 The heteroexchange of CE with triglycerides by CETP leads to the net CE transfer between plasma lipoproteins. 9 This reaction is also one of the key steps of cholesterol transport from the peripheral tissues to the liver. Thus, CETP is involved as much as LCAT in regulation of the plasma HDL level and remodeling of HDL particles. In fact, patients...

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Effect of CETP on the Plasma Lipoprotein Profile in Four Strains of Transgenic Mouse

Cited by 12 publications

References 25 publications

Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse

Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse

Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

Cholesteryl Ester Transfer Protein Expressed in Lecithin Cholesterol Acyltransferase–Deficient Mice

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