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      Molecular Mechanisms of Cellular Cholesterol Efflux*

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          Abstract

          Most types of cells in the body do not express the capability of catabolizing cholesterol, so cholesterol efflux is essential for homeostasis. For instance, macrophages possess four pathways for exporting free (unesterified) cholesterol to extracellular high density lipoprotein (HDL). The passive processes include simple diffusion via the aqueous phase and facilitated diffusion mediated by scavenger receptor class B, type 1 (SR-BI). Active pathways are mediated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, which are membrane lipid translocases. The efflux of cellular phospholipid and free cholesterol to apolipoprotein A-I promoted by ABCA1 is essential for HDL biogenesis. Current understanding of the molecular mechanisms involved in these four efflux pathways is presented in this minireview.

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

          Omar L. Francone, Anne Kennedy, Angel Baldán … (2005)
          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.
          Article 0 comments Cited 202 times – based on 0 reviews     Review now
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            Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses.

            Laurent Yvan-Charvet, Nan Wang, Alan R Tall (2010)
            Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries, but the mechanisms linking cholesterol accumulation in macrophage foam cells to inflammation are poorly understood. Macrophage cholesterol efflux occurs at all stages of atherosclerosis and protects cells from free cholesterol and oxysterol-induced toxicity. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of macrophage cholesterol efflux to serum or HDL in macrophage foam cells, but other less efficient pathways such as passive efflux are also involved. Recent studies have shown that the sterol efflux activities of ABCA1 and ABCG1 modulate macrophage expression of inflammatory cytokines and chemokines as well as lymphocyte proliferative responses. In macrophages, transporter deficiency causes increased signaling via various Toll-like receptors including TLR4. These studies have shown that the traditional roles of HDL and ABC transporters in cholesterol efflux and reverse cholesterol transport are mechanistically linked to antiinflammatory and immunosuppressive functions of HDL. The underlying mechanisms may involve modulation of sterol levels and lipid organization in cell membranes.
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              Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.

              S Xu, Monty Krieger, Helen H. Hobbs … (1996)
              High density lipoprotein (HDL) and low density lipoprotein (LDL) are cholesterol transport particles whose plasma concentrations are directly (LDL) and inversely (HDL) correlated with risk for atherosclerosis. LDL catabolism involves cellular uptake and degradation of the entire particle by a well-characterized receptor. HDL, in contrast, selectively delivers its cholesterol, but not protein, to cells by unknown receptors. Here it is shown that the class B scavenger receptor SR-BI is an HDL receptor. SR-BI binds HDL with high affinity, is expressed primarily in liver and nonplacental steroidogenic tissues, and mediates selective cholesterol uptake by a mechanism distinct from the classic LDL receptor pathway.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biol Chem
                Journal ID (iso-abbrev): J. Biol. Chem
                Journal ID (hwp): jbc
                Journal ID (pmc): jbc
                Journal ID (publisher-id): JBC
                Title: The Journal of Biological Chemistry
                Publisher: American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                ISSN (Print): 0021-9258
                ISSN (Electronic): 1083-351X
                Publication date (Print): 29 August 2014
                Publication date (Electronic): 29 July 2014
                Publication date PMC-release: 29 July 2014
                Volume: 289
                Issue: 35
                Pages: 24020-24029
                Affiliations
                [1]From the Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158
                Author notes
                [1 ] To whom correspondence should be addressed: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd., 11-130 Translational Research Center, Philadelphia, PA 19104-5158. E-mail: mcp3@ 123456mail.med.upenn.edu .
                Article
                Publisher ID: R114.583658
                DOI: 10.1074/jbc.R114.583658
                PMC ID: 4148835
                PubMed ID: 25074931
                SO-VID: 59651ac5-ab2b-482c-9010-2b23f74a1aa0
                Copyright © © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
                License:

                Author's Choice—Final version full access.

                Creative Commons Attribution Unported License applies to Author Choice Articles

                History
                Funding
                Funded by: National Institutes of Health
                Award ID: HL22633
                Categories
                Subject: Minireviews

                ScienceOpen disciplines: Biochemistry
                Keywords: abc transporter,cholesterol,high density lipoprotein (hdl),macrophage,phospholipid,plasma membrane,scavenger receptor,efflux
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: abc transporter, cholesterol, high density lipoprotein (hdl), macrophage, phospholipid, plasma membrane, scavenger receptor, efflux

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