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      Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids[S]

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          Abstract

          Elevated levels of lipoprotein (a) [Lp(a)] are a well-established risk factor for developing CVD. While Lp(a) levels are thought to be independent of other plasma lipoproteins, some trials have reported a positive association between Lp(a) and HDL. Whether Lp(a) has a direct effect on HDL is not known. Here we investigated to determine whether Lp(a) had any effect on the ABCA1 pathway of HDL production in liver cells. Incubation of HepG2 cells with Lp(a) upregulated the PPARγ protein by 1.7-fold and the liver X receptor α protein by 3-fold. This was accompanied by a 1.8-fold increase in ABCA1 protein and a 1.5-fold increase in cholesterol efflux onto apoA1. We showed that Lp(a) was internalized by HepG2 cells, however, the ABCA1 response to Lp(a) was mediated by the selective uptake of oxidized phospholipids (oxPLs) from Lp(a) via the scavenger receptor-B1 and not by Lp(a) internalization per se. We conclude that there is a biological connection between Lp(a) and HDL through the ability of Lp(a)’s oxPLs to upregulate HDL biosynthesis.

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          Most cited references38

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          The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.

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            A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.

            Previous work has implicated PPAR gamma in the regulation of CD36 expression and macrophage uptake of oxidized LDL (oxLDL). We provide evidence here that in addition to lipid uptake, PPAR gamma regulates a pathway of cholesterol efflux. PPAR gamma induces ABCA1 expression and cholesterol removal from macrophages through a transcriptional cascade mediated by the nuclear receptor LXR alpha. Ligand activation of PPAR gamma leads to primary induction of LXR alpha and to coupled induction of ABCA1. Transplantation of PPAR gamma null bone marrow into LDLR -/- mice results in a significant increase in atherosclerosis, consistent with the hypothesis that regulation of LXR alpha and ABCA1 expression is protective in vivo. Thus, we propose that PPAR gamma coordinates a complex physiologic response to oxLDL that involves particle uptake, processing, and cholesterol removal through ABCA1.
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              A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.

              Oxidized phospholipids (OxPLs) on apolipoprotein B-100 (apoB-100) particles are strongly associated with lipoprotein [a] (Lp[a]). In this study, we evaluated whether Lp[a] is preferentially the carrier of OxPL in human plasma. The content of OxPL on apoB-100 particles was measured with monoclonal antibody E06, which recognizes the phosphocholine (PC) headgroup of oxidized but not native phospholipids. To assess whether OxPLs were preferentially bound by Lp[a] as opposed to other lipoproteins, immunoprecipitation and ultracentrifugation experiments, in vitro transfer studies, and chemiluminescent ELISAs were performed. Immunoprecipitation of Lp[a] from human plasma with an apolipoprotein [a] (apo[a])-specific antibody demonstrated that more than 85% of E06 reactivity (i.e., OxPL) coimmunoprecipitated with Lp[a]. Ultracentrifugation experiments showed that nearly all OxPLs were found in fractions containing apo[a], as opposed to other apolipoproteins. In vitro transfer studies showed that oxidized LDL preferentially donates OxPLs to Lp[a], as opposed to LDL, in a time- and temperature-dependent manner, even in aqueous buffer. Approximately 50% of E06 immunoreactivity could be extracted from isolated Lp[a] following exposure of plasma to various lipid solvents. These data demonstrate that Lp[a] is the preferential carrier of PC-containing OxPL in human plasma. This unique property of Lp[a] suggests novel insights into its physiological function and mechanisms of atherogenicity.
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                Author and article information

                Journal
                J Lipid Res
                J. Lipid Res
                jlr
                Journal of Lipid Research
                The American Society for Biochemistry and Molecular Biology
                0022-2275
                1539-7262
                July 2015
                July 2015
                July 2015
                : 56
                : 7
                : 1318-1328
                Affiliations
                []Departments of Surgical Sciences University of Otago , Dunedin, New Zealand
                [§ ]Medicine, Dunedin School of Medicine, University of Otago , Dunedin, New Zealand
                [* ]Department of Biochemistry, University of Otago , Dunedin, New Zealand
                Author notes
                [1 ]To whom correspondence should be addressed. e-mail: sally.mccormick@ 123456otago.ac.nz
                Article
                m056150
                10.1194/jlr.M056150
                4479336
                25852127
                23ef6262-6849-49f4-af62-ff1f6c670d08
                Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

                Author’s Choice—Final version free via Creative Commons CC-BY license.

                Creative Commons Attribution Unported License applies to Author Choice Articles

                History
                : 18 November 2015
                : 4 April 2015
                Categories
                Research Articles

                Biochemistry
                adenosine 5′-triphosphate binding cassette transporter a1,cholesterol efflux,high density lipoprotein,nuclear receptor/liver x receptor,nuclear receptor/peroxisome proliferator-activated receptor

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