HDL, ABC Transporters, and Cholesterol Efflux: Implications for the Treatment of Atherosclerosis

Tall, Alan R.; Yvan‐Charvet, Laurent; Terasaka, Naoki; Pagler, Tamara A.; Wang, Nan

doi:10.1016/j.cmet.2008.03.001

Cited by 498 publications

(415 citation statements)

References 127 publications

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“…Over the past few years, various epidemiological studies have provided ample evidence that increased levels of HDL, by transporting cholesterol from atherosclerotic plaques to liver for excretion, can arrest the progression of CHD (1,2). Subsequent preclinical studies on overexpression of apolipoprotein A-I (apoA-I), the major protein constituent of HDL, have reported significant reduction in CHD risk (3,4). Although raising HDL levels is a longstanding strategy for mitigating CHD risk, the current lipidtargeted therapies, including the usage of statins, fibrates, and niacin, have shown reduced therapeutic potential (5)(6)(7).…”

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confidence: 99%

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Chirasani

Revanasiddappa

Senapati

2016

Journal of Biological Chemistry

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Coronary heart disease (CHD)2 is one of the prime causes of an increase in the mortality rate worldwide. Over the past few years, various epidemiological studies have provided ample evidence that increased levels of HDL, by transporting cholesterol from atherosclerotic plaques to liver for excretion, can arrest the progression of CHD (1, 2). Subsequent preclinical studies on overexpression of apolipoprotein A-I (apoA-I), the major protein constituent of HDL, have reported significant reduction in CHD risk (3, 4). Although raising HDL levels is a longstanding strategy for mitigating CHD risk, the current lipidtargeted therapies, including the usage of statins, fibrates, and niacin, have shown reduced therapeutic potential (5-7). Hence, there is a continuous requirement for new strategies that can elevate HDL levels to halt the progression of CHD.Cholesteryl ester transfer protein (CETP), a plasma glycoprotein with 476 residues, has been found to mediate the transfer of cholesteryl esters (CEs) from HDL to LDL and VLDL as well as the reciprocal transfer of triglycerides (TGs) from LDL and VLDL to HDL (8, 9). The identification of deficient CETP gene levels and correlated high HDL levels in a Japanese population (10 -13) brought CETP into focus as a therapeutic target for controlling HDL levels. Preclinical animal model studies have further substantiated these findings by showing an elevated level of HDL in mice with non-expressing CETP (14 -16). Since then, the inhibition of CETP activity by small molecule inhibitors has been pursued as an active approach to prevent atherosclerosis with varying levels of success at clinical trial phases (17)(18)(19)(20). Given the complexity of lipid metabolism and the pivotal role of CETP in the process, understanding CETP structure, CETP inhibition, and the mechanism by which CETP transfers neutral lipids is of prime importance. The last decade, therefore, has seen the employment of sophisticated techniques, like cryo-EM (21, 22), x-ray (23, 24), and MD simulations (25-28) on this front. Nevertheless, the story of CETP remains far from complete.The crystal structure of CETP (Protein Data Bank entry 2OBD) has been solved with four bound lipid molecules (23). The structure shows two ␤-barrel domains at the N and C termini, each with a twisted ␤-sheet and a long ␣-helix; a central ␤-sheet between the two ␤-barrels; a C-terminal ␣-helix; and a 60-Å-long hydrophobic tunnel occupied by two CE molecules. Additionally, there were two plug-in dioleoylphosphatidylcholine molecules with polar headgroups exposed to plasma and acyl chains buried in the hydrophobic tunnel of CETP. Interestingly, one of the CEs in the hydrophobic tunnel was in the bent conformation, whereas the second CE molecule was in the linear conformation. Recent cryopositive staining EM and optimized negative-staining electron microscopy (OpNS-EM) protocols combined with CETP C terminus-specific polyclonal antibody studies have suggested that CETP penetrates its C-terminal ␤-barrel domain into LDL or VLDL and its N-termi...

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confidence: 99%

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Chirasani

Revanasiddappa

Senapati

2016

Journal of Biological Chemistry

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“…Multiple biological functions of HDL have been identified, whereby HDL may exert antiatherogenic effects (Annema and von Eckardstein 2013;Barter et al 2004;Mineo et al 2006;Rader 2006;, e.g., HDL from healthy subjects has been shown to directly promote endothelial antiapoptotic, anti-inflammatory, and antithrombotic effects (Mineo et al 2006;Nofer et al 2004;Rye and Barter 2008;Tall et al 2008;Yuhanna et al 2001). Accordingly, interventions to improve HDL-C levels and/or HDL function are being intensely evaluated as a potential therapeutic strategy to reduce cardiovascular risk.…”

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confidence: 99%

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

Riwanto

Rohrer

Eckardstein

et al. 2014

Handbook of Experimental Pharmacology

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Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipidmodifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.

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“…Responsive Elements in Their 3′ UTR. Because SREBP-2 and LXR control antagonistic aspects of cellular sterol homeostasis, we hypothesized that miR-33 might be involved in repression of LXR target genes, such as ABCA1 and ABCG1, which are known to promote the efflux of cholesterol from cells (17)(18)(19)(20)(21)(22)(23)(24)(25). Analysis of the 3′ UTR regions of ABCA1 and ABCG1 identified sequences in both genes that are partially complementary to miR-33 sequences (Fig.…”

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miR-33 links SREBP-2 induction to repression of sterol transporters

Marquart

Allen

Ory

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

505

501

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The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.

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HDL, ABC Transporters, and Cholesterol Efflux: Implications for the Treatment of Atherosclerosis

Cited by 498 publications

References 127 publications

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Structural Plasticity of Cholesteryl Ester Transfer Protein Assists the Lipid Transfer Activity

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

miR-33 links SREBP-2 induction to repression of sterol transporters

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