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      Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet

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          Abstract

          Background

          Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.

          Results

          The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.

          Conclusions

          We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.

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          Most cited references19

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          ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.

          Here we demonstrate that the ABC transporter ABCG1 plays a critical role in lipid homeostasis by controlling both tissue lipid levels and the efflux of cellular cholesterol to HDL. Targeted disruption of Abcg1 in mice has no effect on plasma lipids but results in massive accumulation of both neutral lipids and phospholipids in hepatocytes and in macrophages within multiple tissues following administration of a high-fat and -cholesterol diet. In contrast, overexpression of human ABCG1 protects murine tissues from dietary fat-induced lipid accumulation. Finally, we show that cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis.
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            The plasma lecithins:cholesterol acyltransferase reaction.

            J Glomset (1968)
            Evidence for the existence of a plasma lecithin : cholesterol acyltransferase is reviewed with emphasis not only on the lipid reactants, but also on the lipoprotein "substrates" and "products." The cholesteryl esters of all major lipoprotein classes become labeled when plasma is incubated with cholesterol-(14)C. However, the smaller, lecithin-rich high density lipoproteins appear to be preferred substrates. Most studies of factors that influence the acyltransferase reaction have not adequately distinguished between effects on the enzyme and effects on the lipoprotein substrates. However, the fact that cholesterol esterification is diminished in plasma from eviscerated animals or from patients with reduced liver function suggests that the liver may regulate both the level of the enzyme and that of the substrates. Several indications exist that the acyltransferase reaction is the major source of plasma esterified cholesterol in man. Furthermore, the reaction may have a broader, extracellular function. One possibility is that it plays a role in the transport of cholesterol from peripheral tissues to the liver.
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              ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein.

              ABCA1, an ATP-binding cassette transporter mutated in Tangier disease, promotes cellular phospholipid and cholesterol efflux by loading free apoA-I with these lipids. This process involves binding of apoA-I to the cell surface and phospholipid translocation by ABCA1. The goals of this study were to examine the relationship between ABCA1-mediated lipid efflux and apolipoprotein binding and to determine whether phospholipid and cholesterol efflux are coupled. Inhibition of lipid efflux by glybenclamide treatment or by mutation of the ATP-binding cassette of ABCA1 showed a close correlation between lipid efflux, the binding of apoA-I to cells, and cross-linking of apoA-I to ABCA1. The data suggest that a functionally important apoA-I binding site exists on ABCA1 and that the binding site could also involve lipids. After using cyclodextrin preincubation to deplete cellular cholesterol, ABCA1-mediated cholesterol efflux was abolished but phospholipid efflux and the binding of apoA-I were unaffected. The conditioned media from cyclodextrin-pretreated, ABCA1-expressing cells readily promoted cholesterol efflux when added to fresh cells not expressing ABCA1, indicating that cholesterol efflux can be dissociated from phospholipid efflux. Further, using a photoactivatable cholesterol analog, we showed that ABCA1 did not bind cholesterol directly, even though several other cholesterol-binding proteins specifically bound the cholesterol analog. The data suggest that the binding of apoA-I to ABCA1 leads to the formation of phospholipid-apoA-I complexes, which subsequently promote cholesterol efflux in an autocrine or paracrine fashion.
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                Author and article information

                Journal
                Lipids Health Dis
                Lipids in Health and Disease
                BioMed Central
                1476-511X
                2011
                18 January 2011
                : 10
                : 8
                Affiliations
                [1 ]Institute of Atherosclerosis, Taishan Medical University, Taian, Shandong 271000, China
                [2 ]Medical College, Yangzhou University, Yangzhou, Jiangsu 225009, China
                Article
                1476-511X-10-8
                10.1186/1476-511X-10-8
                3031258
                21241519
                8c5d071c-eb94-479b-aff2-3a564beb8acc
                Copyright ©2011 Song et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 December 2010
                : 18 January 2011
                Categories
                Research

                Biochemistry
                Biochemistry

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