Cholesteryl Ester Transfer Protein (CETP) Expression Protects Against Diet Induced Atherosclerosis in SR-BI Deficient Mice

Harder, Christopher J.; Lau, Paulina; Meng, Andrew; Whitman, Stewart C.; McPherson, Ruth

doi:10.1161/01.atv.0000259357.42089.dc

Cited by 50 publications

(28 citation statements)

References 51 publications

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“…In the human situation, an improper functioning of CLA-1 is expected to be compensated for by the presence of CETP, a protein that redistributes cholesteryl esters from HDL to ApoB-containing lipoproteins, including LDL, leading to an alternative uptake route of cholesteryl esters by the adrenals. In our experiments, we confirm that expression of human CETP in SR-BI KO mice indeed leads to the transfer of cholesteryl esters from the relatively large HDL particles to ApoB-containing lipoproteins accessible for LDL receptormediated internalization (32). As already anticipated, the presence of CETP in SR-BI KO mice resulted in an increased delivery of cholesteryl esters from HDL via ApoB-containing lipoproteins to the adrenals.…”

Section: Resultssupporting

confidence: 88%

Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

Hoekstra¹,

Ye²,

Hildebrand³

et al. 2009

Journal of Lipid Research

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Impaired scavenger receptor class B type I (SR-BI)-mediated uptake of HDL-cholesterol esters (HDL-CE) induces adrenal insufficiency in mice. Humans contain an alternative route of HDL-CE clearance, namely through the transfer by cholesteryl ester transfer protein (CETP) to apolipoprotein B lipoproteins for subsequent uptake via the LDL receptor. In this study, we determined whether CETP can compensate for loss of adrenal SR-BI. Transgenic expression of human CETP (CETP Tg) in SR-BI knockout (KO) mice increased adrenal HDL-CE clearance from 33-58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed adrenal hypertrophy due to equally high plasma adrenocorticotropic hormone levels. Adrenal cholesterol levels and plasma corticosterone levels were 38-52% decreased in SR-BI KO mice with and without CETP expression. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level after lipopolysaccharide challenge, leading to an identical .4-fold increased tumor necrosis factor-a response compared with controls. These data indicate that uptake of CE via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal adrenal steroidogenesis. In conclusion, we have shown that CETP-mediated transfer of HDL-CE is not able to reverse adrenal insufficiency in SR-BI knockout mice. Thus, SR-BI-mediated uptake of serum cholesterol is essential for optimal adrenal function.-Hoekstra, M., D. Ye, R. B. Hildebrand, Y. Zhao, B. Lammers, M. Stitzinger, J. Kuiper, T. J. C. Van Berkel, and M. Van Eck. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocor ticoid production.

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Section: Resultssupporting

confidence: 88%

Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

Hoekstra¹,

Ye²,

Hildebrand³

et al. 2009

Journal of Lipid Research

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“…expression diminishes plasma total cholesterol levels and has a major impact on HDL cholesterol content and particle size in SR-BI Ϫ/Ϫ mice (23,24). Under chow diet feeding, we also observed that SR-BI Ϫ/Ϫ /CETP mice exhibited a 1.5-fold decrease in plasma TC as compared with non-CETP transgenic animals ( Table 1).…”

Section: Impact Of Cetp Expression On Plasma Cholesterol Levels and Hsupporting

confidence: 57%

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Bouhassani

Gilibert

Moreau

et al. 2011

Journal of Biological Chemistry

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Scavenger receptor SR-BI significantly contributes to HDL cholesterol metabolism and atherogenesis in mice. However, the role of SR-BI may not be as pronounced in humans due to cholesteryl ester transfer protein (CETP) activity. To address the impact of CETP expression on the adverse effects associated with SR-BI deficiency, we cross-bred our SR-BI conditional knock-out mouse model with CETP transgenic mice. CETP almost completely restored the abnormal HDL-C distribution in SR-BI-deficient mice. However, it did not normalize the elevated plasma free to total cholesterol ratio characteristic of hepatic SR-BI deficiency. Red blood cell and platelet count abnormalities observed in mice liver deficient for SR-BI were partially restored by CETP, but the elevated erythrocyte cholesterol to phopholipid ratio remained unchanged. Complete deletion of SR-BI was associated with diminished adrenal cholesterol stores, whereas hepatic SR-BI deficiency resulted in a significant increase in adrenal gland cholesterol content. In both mouse models, CETP had no impact on adrenal cholesterol metabolism. In diet-induced atherosclerosis studies, hepatic SR-BI deficiency accelerated aortic lipid lesion formation in both CETP-expressing (4-fold) and non-CETP-expressing (8-fold) mice when compared with controls. Impaired macrophage to feces reverse cholesterol transport in mice deficient for SR-BI in liver, which was not corrected by CETP, most likely contributed by such an increase in atherosclerosis susceptibility. Finally, comparison of the atherosclerosis burden in SR-BI liver-deficient and fully deficient mice demonstrated that SR-BI exerted an atheroprotective activity in extra-hepatic tissues whether CETP was present or not. These findings support the contention that the SR-BI pathway contributes in unique ways to cholesterol metabolism and atherosclerosis susceptibility even in the presence of CETP.Epidemiological studies have demonstrated that high density lipoprotein cholesterol is a strong, independent, inverse predictor of the risk of coronary heart disease. High plasma levels of the major apolipoprotein of HDL, APOA-I, have been also shown to predict decreased risk of coronary heart disease. One major atheroprotective mechanism by which HDL/APOA-I may protect against atherosclerosis involves the transport of excess cholesterol from peripheral tissues, including macrophages, to the liver, bile, and eventually feces for excretion, a process known as reverse cholesterol transport.The scavenger receptor SR-BI is an 82-kDa glycosylated plasma membrane protein that binds HDL/APOA-I with high affinity and stimulates the bi-directional flux of cholesterol between cells and extracellular HDL particles. In mice, SR-BI, encodeed by the Scarb1 gene, is a major determinant of HDL metabolism in mice and is protective against atherosclerosis. Indeed, hepatic overexpression of SR-BI markedly reduces plasma HDL-C levels, increases biliary secretion of cholesterol, and decreases atherosclerosis (1-3), whereas deficiency of this receptor resu...

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“…These data are consistent with the recent observation that CETP expression attenuated the development of atherosclerosis in SR-BI-KO mice. 18 These data could also have direct relevance to human physiology. Schwartz and colleagues have demonstrated that in humans the vast majority of HDL CEs that are ultimately secreted into bile are transported to the liver by apoB-containing lipoproteins.…”

Section: Discussionmentioning

confidence: 95%

Expression of Cholesteryl Ester Transfer Protein in Mice Promotes Macrophage Reverse Cholesterol Transport

et al. 2007

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Background-Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B-containing lipoproteins and in humans plays an important role in lipoprotein metabolism. However, the role that CETP plays in mediation of reverse cholesterol transport (RCT) remains unclear. We used a validated in vivo assay of macrophage RCT to test the effect of CETP expression in mice (which naturally lack CETP) on macrophage RCT, including in mice that lack the low-density lipoprotein receptor or the scavenger receptor class B, type I. Method and Results-A vector based on adeno-associated virus serotype 8 (AAV8) with a liver-specific thyroglobulin promoter was used to stably express human CETP in livers of mice and was compared with an AAV8-lacZ control vector. The RCT assay was performed 4 weeks after vector injection and involved the intraperitoneal injection of acetylated low-density lipoprotein cholesterol-loaded and 3 H-cholesterol-labeled J774 macrophages in mice with plasma sampling at several time points, liver and bile sampling at 48 hours, and continuous fecal collection to measure 3 H-sterol as an integrated readout of macrophage RCT. In apobec-1-null mice, CETP expression reduced plasma high-density lipoprotein cholesterol levels but significantly increased fecal 3 H-sterol excretion. In low-density lipoprotein receptor/apobec-1 double-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and had no effect on fecal 3 H-sterol excretion. Finally, in scavenger receptor class B, type I-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and significantly increased fecal 3 H-sterol excretion. Conclusion-The present results demonstrate that CETP expression promotes macrophage RCT in mice, that this effect is dependent on the low-density lipoprotein receptor, and that CETP expression restores to normal the impaired RCT in mice deficient in scavenger receptor class B, type I.

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Cholesteryl Ester Transfer Protein (CETP) Expression Protects Against Diet Induced Atherosclerosis in SR-BI Deficient Mice

Cited by 50 publications

References 51 publications

Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Expression of Cholesteryl Ester Transfer Protein in Mice Promotes Macrophage Reverse Cholesterol Transport

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