ApoA-II Versus ApoA-I

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 21, No. 12ApoA-II Versus ApoA-I Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBApoA-II Versus ApoA-ITwo for One Is Not Always a Good Deal Lawrence W. Castellani and Aldons J. Lusis Lawrence W. CastellaniLawrence W. Castellani Departments of Medicine (L.W.C., A.J.L.) and Microbiology (A.J.L.), Immunology and Molecular Genetics, and Molecular Biology Institute (A.J.L.), University of California, Los Angeles. Search for more papers by this author and Aldons J. LusisAldons J. Lusis Departments of Medicine (L.W.C., A.J.L.) and Microbiology (A.J.L.), Immunology and Molecular Genetics, and Molecular Biology Institute (A.J.L.), University of California, Los Angeles. Search for more papers by this author Originally published15 Mar 2018https://doi.org/10.1161/atvb.21.12.1870Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1870–1872Apolipoprotein A-I (apoA-I), the major protein of HDL, is probably among the most intensively studied of all proteins. It functions in HDL assembly, in the removal of excess cholesterol from cells, and in the transport of cholesterol from peripheral tissues to the liver, a process known as “reverse cholesterol transport.” It is a cofactor for lecithin:cholesterol acyl transferase (LCAT), the enzyme responsible for cholesterol esterification in HDL, and it stabilizes certain antioxidant enzymes, such as serum paraoxonase, that are carried on HDL.1,2 Rare null mutations of apoA-I in human populations are associated with early coronary heart disease,3 and overexpression of apoA-I in transgenic mice protects against atherogenesis.4 An exciting recent development was the 4-angstrom-resolution x-ray structure for the helical part of apoA-I, encompassing residues 44 to 243 (reviewed by Segrest et al5).See page 1977In contrast, apolipoprotein A-II (apoA-II), the second most abundant protein of HDL, has no known function, and it has been the subject of few detailed studies. Its presence in HDL has been reported to decrease,6 or have no influence on, cholesterol efflux from cells,7,8 nor is it a cofactor for any known enzyme. Rare individuals lacking apoA-II appear to have normal plasma lipids.9 In fact, all of the known effects of apoA-II are deleterious. In studies with mice and humans, apoA-II levels have been associated with increased susceptibility to atherosclerosis,10–13 increased free fatty acid levels,14,15 increased body fat,15,16 and increased insulin resistance.15,17 Undoubtedly, apoA-II has some unknown beneficial functions, possibly related to fatty acid metabolism or host defense.In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Holvoet et al18 report studies of a chimeric protein between apoA-I and apoA-II, in which the central domain of apoA-I (Arg123-Tyr166) is substituted with the Ser12-Ala75 segment of apoA-II. Mice expressing this chimeric protein were compared with transgenic mice expressing similar levels of apoA-I. Although cholesterol levels were similar between the apoA-I/apoA-II transgenic mice and the apoA-I transgenic mice, atherosclerotic lesions (studied in an apoE null background) were much larger in apoA-I/apoA-II transgenics (about 2.7-fold). The apoA-I/apoA-II transgenic mice also exhibited increased macrophage homing in the aortic root (2.7-fold) and increased macrophage to smooth muscle cell ratios in lesions (2.1-fold). Thus, although apoA-I and apoA-II are close cousins, both consisting largely of a common lipid-association structural motif, the substitution of the central region of apoA-I by a portion of apoA-II has major functional consequences. The results suggest that the region is critical for functions involved in oxidative stress and inflammation but not cholesterol transport. A summary of the effects of apoA-I, apoA-II, and the apoA-I/A-II chimera are given in the Table. Table 1. Comparison of Effects of ApoAI, ApoAII, and the ApoAI/ApoAII Chimera as Studied in Transgenic MiceApoA-IApoA-IIApoA-I/ApoA-II ChimeraFFA indicates free fatty acid.Plasma HDL cholesterolIncreased because it promotes formation of nascent HDL and activates LCATIncreased because of impaired catabolismNo effectPlasma triglyceridesApoA-I Milano variant increases triglycerides in humans and transgenic miceIncreased because increased production and decreased clearance of VLDLNo effectPlasma FFA levelsNo known effectsIncreased possibly because of altered FFA metabolism mediated through CD36 or as a consequence of peripheral insulin resistanceNo effectSR-BI receptorIncreases binding and cholesterol exchange compared with apoA-IIDecreases HDL binding and cholesterol exchange?CD36 receptorIncreased binding and cholesterol exchange compared with apoA-IIDecreases HDL binding and cholesterol exchange?ABCA-1 receptorSimilar binding as apoA-IISimilar binding as apoA-I?AtherosclerosisProtects: promotes reverse cholesterol transport; stabilizes HDL-associated anti-oxidant enzymes, PON1 and PAF-AHPromotes: inhibits several aspects of reverse cholesterol transport and lowers PON1 activity in transgenic micePromotes: increases oxidative stress through a reduction in the HDL anti-oxidant enzymes PON1 and PAF-AHInsulin resistanceNo known effectsClearly promotes insulin resistance in mice; probably promotes insulin resistance in humans?Lipid-binding affinityLower affinity than apoA-IIHigher affinity than apoA-INo effectReverse cholesterol transportPromotes all aspectsEither has no effect or impairs all aspectsNo effectParaoxonaseIncreases PON1 activityPON1 activity reduced by 50%, based on HDL protein, in apoA-II transgenic micePON1 activity reduced compared with apoA-I transgenic mice on an apoE-null backgroundPAF acetyl-hydrolaseIncreases activity in apoA-I transgenic mice; activity decreased in apoA-I variantsActivity not affected in apoA-II transgenic micePAF-AH activity reducedOxidized stressAnti-oxidant, partly through stabilizing PON1 and PAF-AHPro-oxidant: lowers PON1 activity and increases apoB containing lipoproteinsPro-oxidant: decreased PAF-AH activityHow does apoA-I transport lipids and contribute to the anti-inflammatory properties of HDL? ApoA-I can interact with phospholipids to form discoidal (hockey puck-shaped) complexes that are precursors of mature, spherical HDL. These apoA-I-only (LpA-I) particles subsequently become loaded with cholesteryl esters through the action of LCAT and acquire other lipoproteins, including apoA-II (LpA-I, A-II) (reviewed by Frank and Marcel19). Previous studies have revealed domains of apoA-I associated with various functions. The N-terminus (residues 1 to 43) forms a globular domain while the C-terminus (residues 44 to 241) consists largely of a series of amphipathic α-helices that that have a narrow hydrophobic face on one side and a hydrophilic face on the other. Mutagenesis and other approaches have defined a number of regions as important in lipid binding: residues 44 to 65, 100 to 121, 122 to 143, and 210 to 241. Residues 144 to 186, however, contribute relatively little to lipid binding. The LCAT activation domain encompasses helices 144 to 165 and 166 to 186. The C-terminal region of apoA-I seems to be important for the interaction of lipid-free apoA-I with macrophages and for specific lipid efflux.If, indeed, the amphipathic helices are a key to the antiatherogenic functions of apoA-I, why then does apoA-II not protect similarly, since it is also composed largely of amphipathic helices? The answer seems to be that the precise sequence of the helices, not simply their amphipathic nature, is crucial for the functions of apoA-I.20 It is probably significant that apoA-I helices contain both Lys and Arg as positively charged amino acids, whereas apoA-II contains only Lys. Some studies suggest that that Arg residues at the polar-nonpolar interface of apoA-I are important for LCAT activation.21 There are also other differences between the helices of apoA-I and apoA-II, such as the presence of bulky Ile and Phe residues in apoA-II. Such differences could conceivably influence interactions with lipids, cell membranes, or proteins. It is noteworthy that Anantharmaiah and colleagues20 have produced α-helical peptides that form peptido-lipid complexes similar to those formed by intact apoA-I. Like intact apoA-I, these peptides are capable of inhibiting atherogenesis and of clearing oxidized pro-inflammatory lipids. Thus, it seems that certain short amphipathic helical domains of apoA-I can mimic at least some of the properties of intact apoA-I.It is likely that the effects of the A-I/A-II chimera on atherosclerosis and inflammation are caused, in part, by interactions with two anti-inflammatory enzymes carried on HDL, platelet activating factor acetyl hydrolase (PAF-AH) and serum paraoxonase (PON1). In tissue cultures of vascular cells, HDL isolated from transgenic mice overexpressing apoA-II promoted the formation of lipid hydroperoxides and the activation of inflammatory genes in cells.8 Such apoA-II transgenic HDL had only about 50% of the PON1 activity compared with HDL from nontransgenic mice, and PON1 supplementation of HDL from the apoA-II transgenic mice significantly reduced the proinflammatory properties of the HDL.8 Overexpression of apoA-I, however, resulted in increased PON1 and PAF-AH activities.22 Although plasma paraoxonase activities were not determined in the present study, the activity of PAF-AH was significantly reduced. It would seem that the region of apoA-I substituted in the present study by Holvoet et al18, is important for stabilizing PAF-AH activity and possibly paroxonase. Other regions of apoA-I important for stabilizing paraoxonase have been identified by using mutagenesis studies.23The increased lesion formation observed in the present study, as well as in the apoA-II transgenic mice, may also be mediated in part through interaction with cell surface receptors, and the scavenger receptor CD36 is a good candidate. The CD36 receptor is expressed in a variety of cell types including endothelial cells, and it binds both native and oxidized lipoproteins. The latter have been demonstrated to induce a variety of pro-inflammatory genes through a second messenger system involving nuclear factor-κB.24 HDL from apoA-II transgenic mice exhibited reduced binding to the CD36 receptor.15 Recent studies with apoA-II transgenic mice provide strong evidence that HDL can induce insulin resistance in skeletal muscle,15 suggesting such receptor interactions. It is interesting to speculate that HDL with the chimeric apoA-I may exhibit altered interaction with CD36.Elevated expression of apoA-II dramatically increased plasma levels of VLDL, LDL, and remnant particles, most likely through both increased synthesis and decreased catabolism.8,10,15 Still another potential pathway by which the apoA-I/A-II chimera may influence atherosclerosis and vascular inflammation is via effects on triglyceride-rich lipoproteins. Overexpression of apoA-II also resulted in displacement of apoE and apoCs from HDL to VLDL, LDL, and remnant-sized particles, which may contribute to their altered catabolism.10 Although in the present study no differences in plasma lipid concentrations were observed, βVLDL from the apoA-I/A-II transgenic mice were significantly different from βVLDL from the apoA-I transgenic mice with respect to stimulation of macrophage homing.These results by Holvoet and colleagues18 remind us that we still have much to learn about the functions of apoA-I and apoA-II. Most studies have focused on the lipid transport aspects of these molecules, but it is clear that functions independent of lipid transport are likely to be very important with respect to atherogenesis. In this regard, it is interesting that a recent report indicates that ABCA-1-null mice have a near absence of HDL cholesterol, but, nevertheless, have normal biliary secretion rates of cholesterol, bile salts, and phospholipids.25 This observation requires further study, but it suggests that the anti-inflammatory properties of HDL may be of primary importance in atherosclerosis.FootnotesCorrespondence to Lawrence W. Castellani, PhD, Department of Medicine/Division of Cardiology, 47-123 CHS, University of California, Los Angeles, CA 90095. E-mail [email protected] References 1 Sviridov D, Hoang A, Sawyer WH, Fidge NH. Identification of a sequence of apolipoprotein A-I associated with the activation of lecithin:cholesterol acyltransferase. J Biol Chem. 2000; 275: 19707–19712.CrossrefMedlineGoogle Scholar2 Sorenson RC, Bisgaier CL, Aviram M, Hsu C, Billecke S, La Du BN. 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December 2001Vol 21, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/atvb.21.12.1870PMID: 11742857 Originally publishedMarch 15, 2018 PDF download Advertisement