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      Synthetic High-Density Lipoprotein-Mediated Targeted Delivery of Liver X Receptors Agonist Promotes Atherosclerosis Regression

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          Abstract

          Targeting at enhancing reverse cholesterol transport (RCT) is apromising strategy for treating atherosclerosis via infusion of reconstitute high density lipoprotein (HDL) as cholesterol acceptors or increase of cholesterol efflux by activation of macrophage liver X receptors (LXRs). However, systemic activation of LXRs triggers excessive lipogenesis in the liver and infusion of HDL downregulates cholesterol efflux from macrophages. Here we describe an enlightened strategy using phospholipid reconstituted apoA-I peptide (22A)-derived synthetic HDL (sHDL) to deliver LXR agonists to the atheroma and examine their effect on atherosclerosis regression in vivo. A synthetic LXR agonist, T0901317 (T1317) was encapsulated in sHDL nanoparticles (sHDL-T1317). Similar to the T1317 compound, the sHDL-T1317 nanoparticles upregulated the expression of ATP-binding cassette transporters and increased cholesterol efflux in macrophages in vitro and in vivo. The sHDL nanoparticles accumulated in the atherosclerotic plaques of ApoE-deficient mice. Moreover, a 6-week low-dose LXR agonist-sHDL treatment induced atherosclerosis regression while avoiding lipid accumulation in the liver. These findings identify LXR agonist loaded sHDL nanoparticles as a promising therapeutic approach to treat atherosclerosis by targeting RCT in a multifaceted manner: sHDL itself serving as both a drug carrier and cholesterol acceptor and the LXR agonist mediating upregulation of ABC transporters in the aorta.

          Highlights

          • Macrophage liver X receptors (LXRs) have been established as potential therapeutic targets for treatment of atherosclerosis.

          • Synthetic high-density lipoprotein nanoparticles deliver LXR agonists to the atheroma and promote atherosclerosis regression.

          • Systemic administration of LXR ligands (LXR-L) has stalled because of their side effects, especially increased hepatic lipogenesis.

          Macrophage LXRs have been established as potential therapeutic targets for treatment of atherosclerosis based on the beneficial effects on enhance of reverse cholesterol transport (RCT). However, systemic activation of LXRs triggers excessive lipogenesis in the liver. Synthetic high-density lipoprotein (sHDL) nanoparticles can deliver LXR agonists to the atheroma and promote atherosclerosis regression by targeting RCT in a multifaceted manner: sHDL itself serving as both a drug carrier and cholesterol acceptor and the LXR agonist enhancing cholesterol efflux in the macrophages in the atherosclerotic plaques.

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          Most cited references32

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          Synthetic LXR ligand inhibits the development of atherosclerosis in mice.

          The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR(-/-) mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE(-/-) mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR(-/-) and apoE(-/-) mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.
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            The roles of different pathways in the release of cholesterol from macrophages.

            Cholesterol efflux occurs by different pathways, including transport mediated by specific proteins. We determined the effect of enriching cells with free cholesterol (FC) on the release of FC to human serum. Loading Fu5AH cells with FC had no effect on fractional efflux, whereas enriching mouse peritoneal macrophages (MPMs) resulted in a doubling of fractional efflux. Efflux from cholesterol-normal MPM and Fu5AH cells to 15 human sera correlated well with HDL parameters. However, these relationships were reduced or lost with cholesterol-loaded MPMs. Using macrophages from scavenger receptor class B type I (SR-BI)-, ABCA1-, and ABCG1-knockout mice, together with inhibitors of SR-BI- and ABCA1-mediated efflux, we were able to quantitate efflux upon loading macrophages with excess cholesterol and to establish the contributions of the various efflux pathways in cholesterol-normal and -enriched cells. The removal of ABCA1 had essentially no effect on the total efflux when cell cholesterol levels were normal. However, in cholesterol-enriched cells, the removal of ABCA1 reduced efflux by 50%. Approximately 20% of the efflux stimulated by FC-loading MPM is attributable to ABCG1. The SR-BI contribution to efflux was small. Another pathway that is present in all cells is aqueous diffusion. Our studies demonstrate that this mechanism is one of the major contributors to efflux, particularly in cholesterol-normal cells.
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              Identification of macrophage liver X receptors as inhibitors of atherosclerosis.

              Recent studies have identified the liver X receptors (LXR alpha and LXR beta) as important regulators of cholesterol metabolism and transport. LXRs control transcription of genes critical to a range of biological functions including regulation of high density lipoprotein cholesterol metabolism, hepatic cholesterol catabolism, and intestinal sterol absorption. Although LXR activity has been proposed to be critical for physiologic lipid metabolism and transport, direct evidence linking LXR signaling pathways to the pathogenesis of cardiovascular disease has yet to be established. In this study bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. Our results demonstrate that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimics many aspects of Tangier disease, a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identify LXRs as targets for intervention in cardiovascular disease.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                20 December 2017
                February 2018
                20 December 2017
                : 28
                : 225-233
                Affiliations
                [a ]Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States
                [b ]Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, United States
                [c ]Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, United States
                [d ]Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
                Author notes
                [* ]Corresponding authors at: Bldg 26, Room 345S, 2800 Plymouth Road, Ann Arbor, MI 48109, United States.Bldg 26, Room 345S2800 Plymouth RoadAnn ArborMI48109United States yanhongg@ 123456umich.edu echenum@ 123456umich.edu
                [** ]Correspondence to: A. Schwendeman, Bldg 10, Room 109, 2800 Plymouth Road, Ann Arbor, MI 48109, United States.Bldg 10, Room 1092800 Plymouth RoadAnn ArborMI48109United States annaschw@ 123456umich.edu
                [1]

                Denote equal contribution.

                Article
                S2352-3964(17)30502-9
                10.1016/j.ebiom.2017.12.021
                5835545
                29361501
                490fa855-f14d-4ff3-9b26-51c15e80f848
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 17 October 2017
                : 6 December 2017
                : 18 December 2017
                Categories
                Research Paper

                atherosclerosis,liver x receptors,high-density lipoprotein,reverse cholesterol transport,macrophage

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