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Stafforini DM Ref: Enzymes, 38:157, 2015 : PubMed ESTHER: Stafforini_2015_Enzymes_38_157 PubMedSearch: Stafforini 2015 Enzymes 38 157 PubMedID: 26612652 Abstract This chapter is focused on the role of the plasma form of platelet-activating factor-acetylhydrolase (PAF-AH), heretofore referred to as PAF-AH, in tumorigenic responses. Biochemical and other properties of this enzyme were discussed in detail in chapter "Plasma PAF-AH (PLA2G7): Biochemical Properties, Association with LDLs and HDLs, and Regulation of Expression" by Stafforini and in other chapters. Although phospholipases tend not to be drivers of tumorigenesis themselves, these enzymes and the lipid mediators whose levels they regulate interact with a variety of oncogenes and tumor suppressors [1]. Like other phospholipases, the functions of PAF-AH in cancer likely are related to its ability to regulate the levels of lipid mediators that participate in cellular processes related to initial tumorigenic events (e.g., proliferation, growth, inflammation) and/or spreading of the disease (e.g., matrix metalloproteinase secretion, actin cytoskeleton reorganization, migration, and angiogenesis) [1]. The importance of substrates and products of PAF-AH on key cellular functions has been evaluated in cell-based analyses which revealed that these metabolites can have pro- and antitumorigenic functions. Studies in genetically engineered mice lacking PAF-AH expression and genetic manipulation of PAF-AH levels in cancer cells demonstrated diverse functions of the protein in models of melanoma, prostate cancer, colon cancer, and others. The following sections highlight lessons learned from studies in cell lines and in mouse models regarding the diversity of functions of PAF-AH in cancer, and the potential of PAFAH transcripts, protein, and/or activity levels to become cancer biomarkers and therapeutic targets. Title: Plasma PAF-AH (PLA2G7): Biochemical Properties, Association with LDLs and HDLs, and Regulation of Expression Stafforini DM Ref: Enzymes, 38:71, 2015 : PubMed ESTHER: Stafforini_2015_Enzymes_38_71 PubMedSearch: Stafforini 2015 Enzymes 38 71 PubMedID: 26612648 Abstract This chapter is focused on the plasma form of PAF-acetylhydrolase (PAF-AH), a lipoprotein-bound, calcium-independent phospholipase A2 activity also referred to as lipoprotein-associated phospholipase A2 and PLA2G7. PAF-AH catalyzes the removal of the acyl group at the sn-2 position of PAF and truncated phospholipids generated in settings of inflammation and oxidant stress. Here, I discuss current knowledge related to the structural features of this enzyme, including the molecular basis for association with lipoproteins and susceptibility to oxidative inactivation. The circulating form of PAF-AH is constitutively active and its expression is upregulated by mediators of inflammation at the transcriptional level. Several new mechanisms of regulation have been identified in recent years, including effects mediated by PPARs, VEGFR, and the state of cellular differentiation. Moreover, I discuss recent studies describing significant variations in the structure and regulation of PAF-AH from diverse species, which is likely to have important implications for the function of this enzyme in vivo. Title: Unraveling the PAF-AH/Lp-PLA2 controversy Stafforini DM, Zimmerman GA Ref: J Lipid Res, 55:1811, 2014 : PubMed ESTHER: Stafforini_2014_J.Lipid.Res_55_1811 PubMedSearch: Stafforini 2014 J.Lipid.Res 55 1811 PubMedID: 25007789 Inhibitor(s) related to this paper: Darapladib Abstract The secreted or plasma form of platelet-activating factor acetylhydrolase (PAF-AH), also known as lipoprotein-associated phospholipase A2 (Lp-PLA2) or phospholipase A2 group 7 (PLA2G7), is a member of the PLA2 superfamily of enzymes that circulates in blood in association with lipoproteins, and is found in atherosclerotic lesions. This enzyme was discovered in the early 1980s based on its ability to hydrolyze the pro-inflammatory glycerophospholipid PAF, and was thus proposed to have anti-inflammatory properties. In subsequent years, it was recognized that PAF-AH hydrolyzes glycerophospholipids containing short and/or oxidized functionalities at the sn-2 position, with no preference for the type of linkage at the sn-1 position, i.e., alkyl versus acyl. Substrate hydrolysis catalyzed by PAF-AH generates lysoPAF/lyso phosphatidylcholine (lysoPC) and short and/or oxidized fatty acids, many of which also have been reported to have pro-inflammatory and pro-oxidative activities. These observations fueled multiple investigations that led to controversial views regarding the role of PAF-AH in human physiology and disease. Notably, the hypothesis that PAF-AH might actively contribute to vascular inflammation during atherogenesis owing to its ability to generate pro-inflammatory substances led to the proposition that inhibition of the activity could offer vascular protection in addition to that afforded by cholesterol lowering agents. A number of reversible PAF-AH inhibitors were developed in the pharmaceutical industry and one of them, darapladib, has been extensively tested in vitro and in vivo . Moreover, GlaxoSmithKline sponsored three darapladib clinical trials that yielded relatively consistent results. In this issue of the Journal of Lipid Research, ( Marathe et al.) provide their views on the role of PAF-AH in inflammatory responses, with a focus on CVD. The authors make several key points and offer a seldom encountered perspective that takes into consideration the origin and wide range of substrates hydrolyzed by PAF-AH, the physiological meaning of studies involving one of the products of the reaction (lysoPAF/lysoPC), and the impact of receptors that recognize substrates and products on downstream signaling events. The authors present several lines of evidence arguing against a pro-atherogenic role for PAF-AH and its products, and suggest that elevated enzyme levels reflect a response to the pro-inflammatory/pro-oxidative stress that is typical of atherosclerosis. Their conclusions are timely and consistent with results from recent clinical trials in humans. In the Integrated Biomarker and Imaging Study 2 phase II trial involving patients with coronary heart disease, the PAF-AH inhibitor darapladib did not meet prespecified primary and secondary endpoints that included effects on coronary atheroma deformability, composition and size, CRP levels, and total atheroma volume. While darapladib administration inhibited necrotic core expansion, this conclusion was reached only by fine interpretation of imaging data. Nonetheless, the finding provided, in part, the basis to conduct two phase III trials. The recently published STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial showed that darapladib did not affect the primary composite endpoint that included time to cardiovascular death, myocardial infarction, or stroke in patients with stable coronary heart disease. Similarly, results recently reported from SOLID-TIMI (Stabilization of Plaques using Darapladib-Thrombolysis in Myocardial Infarction) revealed no reduction in major coronary events when added to standard of care after an acute coronary syndrome. An important lesson learned from the outcome of studies using darapladib is related to the necessity of gathering rigorous scientific evidence supporting a solid rationale to justify launching clinical trials in humans. Arguably, this was not the case for darapladib. Mechanistically, the trials were largely based on laboratory studies that investigated pro-inflammatory functions of lysoPC and, to a lesser extent, oxidized fatty acids. Marathe et al. appropriately describe two major potential problems associated with interpretation of studies using exogenous lysoPC. First, trace amounts of PAF and/or related phospholipids have been shown to contaminate numerous commercial lysoPC preparations. This problem may have affected multiple studies in which contaminating PAF could have accounted for responses incorrectly ascribed to lysoPC . Marathe et al. also point out that lysoPC occurs naturally at very high concentrations in body fluids and atherosclerotic tissues. Its amphipathic nature and detergent-like properties can induce nonspecific cellular responses. In physiological settings, these effects are in large part prevented because lysoPC forms complexes with serum proteins, immunoglobulins, and plasma membranes. Thus, total lysoPAF/lysoPC concentrations do not relate to bioavailability and it is highly unlikely that the relatively small amounts of free lysoPAF/lysoPC generated by PAF-AH contribute to inflammatory responses in the vasculature. A second issue to reflect upon is the importance of interpreting correlative studies appropriately. Strong positive correlations between plasma PAF-AH and LDL cholesterol levels were established approximately 30 years ago. Plasma PAF-AH associates with cholesterol-containing LDL particles; as expected, enzyme levels decrease in response to statin treatment. Many prospective population-based studies confirmed tight links between increased plasma PAF-AH levels and increased cardiovascular risk (2834). Predictably, the strength of this association is highly reduced after adjustment for baseline concentrations of lipids and apolipoproteins, particularly apoB levels. These observations demonstrate that elevated circulating levels of PAF-AH (Lp-PLA2, the FDA-cleared diagnostic test is called PLAC) are associated with atherosclerosis. But such observations support neither causal nor protective roles for PAF-AH in the disease process. In contrast, the fact that partial inhibition of PAF-AH with darapladib did not prevent adverse events in coronary heart disease patients argues against active contribution of the enzyme to plaque vulnerability and major adverse cardiovascular complications such as heart attack, stroke, and death. A third consideration is that the relationship between PAF-AH, PAF, and PAF-like substrates and products generated to various extents in settings of inflammation and oxidant stress is incompletely understood. In this regard, Marathe et al. present a hypothetical model suggesting that the relative abundance of alkyl versus acyl PAF may determine whether PAF-AH has pro- or anti-inflammatory/atherogenic functions. While alkyl and acyl PAF and PAF-like lipids have been reported to be continuously generated, alkyl-linked species are functionally more potent owing to their higher affinity for the PAF receptor (PAF-R), a G protein-coupled receptor that transduces PAF signals. According to Marathe et al., acyl-linked PAF-like analogs are less potent and could potentially behave as relative PAF-R antagonists, although this remains to be shown experimentally. If this scenario is correct, hydrolysis of acyl-linked PAF-like lipids by PAF-AH could effectively decrease the levels of PAF-R antagonists, potentially increasing pro-inflammatory/atherogenic activities. This interesting and provocative model will require future pharmacologic and molecular studies, including targeted silencing of PAF biosynthetic and hydrolytic pathways. It is important to also consider, however, that PAF-AH substrates often elicit biological activity in PAF-R-independent manners. Moreover, it will be important to establish whether the truncated/oxidized sn-2 fatty acids released by PAF-AH also contribute to its physiologic function. Adding to the complexity is that in this process truncated oxidized phospholipids (OxPLs), which are potent pro-inflammatory molecules, are degraded by this enzymatic activity. While darapladib failed to reach all of its primary endpoints, the inhibitor showed some efficacy when administered in experimental animal models and humans. Indeed, darapladib and related compounds significantly decreased atherosclerotic coronary lesion development, reduced macrophage content in vascular lesions, and attenuated plaque inflammation in various animal models. In interpreting these studies, it is important to establish whether darapladib exerted biologic effects by inhibiting PAF-AH activity or by some other mechanism. Careful analysis of changes in lipid metabolites suggests the possibility that darapladib may have antioxidant and/or other off target effects. Although darapladib treatment was associated with reduced content of lysoPC in pig atherosclerotic lesions, it did not affect the levels of truncated OxPL species known to be metabolized by PAF-AH, and did not alter serum PAF levels in two murine models of atherosclerosis. Besides its effects on lipid metabolism, darapladib treatment decreased caspase-3 and caspase-8 activity in vivo), and a compound related to darapladib (SB222657) inhibited macrophage apoptosis induced by oxidized LDL in vitro. These observations raise the possibility that darapladib has activities in addition to its inhibitory effects on PAF-AH. It is thus conceivable that these effects may contribute to its in vivo activities. Regardless, darapladib has taught us that partial inhibition of PAF-AH does not appear to have major impact on vascular events and that the enzyme is unlikely to be the sought-after cholesterol-independent biomarker and target whose inhibition would further decrease morbidity and mortality of patients with vascular disease. The fact that darapladib-mediated partial inhibition of PAF-AH did not reduce coronary events does not, however, suggest that the future of anti-inflammatory heart drugs is dimmed, as recently suggested . The activity of PAF-AH has not been shown to lead to a net increase in pro-inflammatory lipid mediator levels in vascular settings. Regrettably, the enzyme is often referred to as a pro-inflammatory protein despite the fact that it has anti-inflammatory properties, as demonstrated in the original article describing cloning of the gene and characterization of the enzyme. Deciphering the physiologic roles of PAF-AH continues to be a challenge for investigators across academia and the private sector alike, and a number of issues remain to be resolved. For example, it is not clear whether PAF-AH functions in the circulation, in atherosclerotic plaques and other tissues, or both. A study using mice lacking PAF-AH expression suggested that the enzyme may not function in the circulation and that substrate transport to the intracellular compartment may be required before hydrolysis occurs. In addition, the relationship between circulating and tissue PAF-AH and OxPLs has not been critically evaluated, and this issue raises important questions regarding the impact of enzyme, substrate, and products in different biologic compartments. The article by Marathe et al. discusses some of these variables in the intricate biochemistry and biology of PAF-AH, PAF, and related lipids. Title: Determination of phospholipase activity of PAF acetylhydrolase Stafforini DM, McIntyre TM Ref: Free Radic Biol Med, 59:100, 2013 : PubMed ESTHER: Stafforini_2013_Free.Radic.Biol.Med_59_100 PubMedSearch: Stafforini 2013 Free.Radic.Biol.Med 59 100 PubMedID: 22659315 Abstract This article presents a radiometric assay to determine the enzymatic activity of platelet-activating factor (PAF) acetylhydrolase (PAF-AH), also known as lipoprotein-associated phospholipase A2 and phospholipase A2 group 7A. The method is based on the release of radioactively labeled acetate from sn-2-labeled PAF and separation of substrate and product using reversed-phase column chromatography on octadecyl silica gel cartridges. The assay is fast, convenient, reproducible, sensitive, and inexpensive. The instrumentation required includes standard laboratory equipment and a liquid scintillation counter. The assay is also useful to determine the activity of intracellular PAF-AH (PAF-AH II), provided that a few modifications are included. The enzymatic activity determined using PAF as the substrate is a direct indication of the ability of plasma samples, purified preparations, and cellular and tissue lysates to hydrolyze short- and medium-chain phospholipids that may or may not harbor oxidized functionalities. In addition, the assay can be used to test the suitability of other phospholipids, including species containing oxidized, long-chain sn-2 fatty acyl groups, as PAF-AH substrates. This versatile assay can be used to accurately determine PAF-AH activity in biological samples and preliminarily assess affinity and efficiency of the hydrolysis of potential substrates present in complex mixtures. Title: Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2 Rosenson RS, Stafforini DM Ref: J Lipid Res, 53:1767, 2012 : PubMed ESTHER: Rosenson_2012_J.Lipid.Res_53_1767 PubMedSearch: Rosenson 2012 J.Lipid.Res 53 1767 PubMedID: 22665167 Abstract Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase (PAF-AH), is a unique member of the phospholipase A(2) superfamily. This enzyme is characterized by its ability to specifically hydrolyze PAF as well as glycerophospholipids containing short, truncated, and/or oxidized fatty acyl groups at the sn-2 position of the glycerol backbone. In humans, Lp-PLA(2) circulates in active form as a complex with low- and high-density lipoproteins. Clinical studies have reported that plasma Lp-PLA(2) activity and mass are strongly associated with atherogenic lipids and vascular risk. These observations led to the hypothesis that Lp-PLA(2) activity and/or mass levels could be used as biomarkers of cardiovascular disease and that inhibition of the activity could offer an attractive therapeutic strategy. Darapladib, a compound that inhibits Lp-PLA(2) activity, is anti-atherogenic in mice and other animals, and it decreases atherosclerotic plaque expansion in humans. However, disagreement continues to exist regarding the validity of Lp-PLA(2) as an independent marker of atherosclerosis and a scientifically justified target for intervention. Circulating Lp-PLA(2) mass and activity are associated with vascular risk, but the strength of the association is reduced after adjustment for basal concentrations of the lipoprotein carriers with which the enzyme associates. Genetic studies in humans harboring an inactivating mutation at this locus indicate that loss of Lp-PLA(2) function is a risk factor for inflammatory and vascular conditions in Japanese cohorts. Consistently, overexpression of Lp-PLA(2) has anti-inflammatory and anti-atherogenic properties in animal models. This thematic review critically discusses results from laboratory and animal studies, analyzes genetic evidence, reviews clinical work demonstrating associations between Lp-PLA(2) and vascular disease, and summarizes results from animal and human clinical trials in which administration of darapladib was tested as a strategy for the management of atherosclerosis. Title: Identification of a domain that mediates association of platelet-activating factor acetylhydrolase with high density lipoprotein Gardner AA, Reichert EC, Topham MK, Stafforini DM Ref: Journal of Biological Chemistry, 283:17099, 2008 : PubMed ESTHER: Gardner_2008_J.Biol.Chem_283_17099 PubMedSearch: Gardner 2008 J.Biol.Chem 283 17099 PubMedID: 18434304 Gene_locus related to this paper: human-PLA2G7 Abstract The plasma form of platelet-activating factor (PAF) acetylhydrolase (PAF-AH), also known as lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inactivates potent lipid messengers such as PAF and modified phospholipids generated in settings of oxidant stress. In humans, PAF-AH circulates in blood in fully active form and associates with high and low density lipoproteins (HDL and LDL). Several studies suggest that the location of PAF-AH affects both the catalytic efficiency and the function of the enzyme in vivo. The distribution of PAF-AH among lipoproteins varies widely among mammals. Here, we report that mouse and human PAF-AHs associate with human HDL particles of different density. We made use of this observation in the development of a binding assay to identify domains required for association of human PAF-AH with human HDL. Sequence comparisons among species combined with domain-swapping and site-directed mutagenesis studies led us to the identification of C-terminal residues necessary for the association of human PAF-AH with human HDL. Interestingly, the region identified is not conserved among PAF-AHs, suggesting that PAF-AH interacts with HDL particles in a manner that is unique to each species. These findings contribute to our understanding of the mechanisms responsible for association of human PAF-AH with HDL and may facilitate future studies aimed at precisely determining the function of PAF-AH in each lipoprotein particle. Title: Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma Stafforini DM, Numao T, Tsodikov A, Vaitkus D, Fukuda T, Watanabe N, Fueki N, McIntyre TM, Zimmerman GA and Prescott SM <1 more author(s)> Stafforini DM, Numao T, Tsodikov A, Vaitkus D, Fukuda T, Watanabe N, Fueki N, McIntyre TM, Zimmerman GA, Makino S, Prescott SM (- 1) Ref: J Clinical Investigation, 103:989, 1999 : PubMed ESTHER: Stafforini_1999_J.Clin.Invest_103_989 PubMedSearch: Stafforini 1999 J.Clin.Invest 103 989 PubMedID: 10194471 Gene_locus related to this paper: human-PLA2G7 Abstract Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma. Title: Platelet-activating factor acetylhydrolases Stafforini DM, McIntyre TM, Zimmerman GA, Prescott SM Ref: Journal of Biological Chemistry, 272:17895, 1997 : PubMed ESTHER: Stafforini_1997_J.Biol.Chem_272_17895 PubMedSearch: Stafforini 1997 J.Biol.Chem 272 17895 PubMedID: 9218411 Gene_locus related to this paper: bovin-paf2, human-PAFAH2 Title: Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase Stafforini DM, Satoh K, Atkinson DL, Tjoelker LW, Eberhardt C, Yoshida H, Imaizumi T, Takamatsu S, Zimmerman GA and Prescott SM <2 more author(s)> Stafforini DM, Satoh K, Atkinson DL, Tjoelker LW, Eberhardt C, Yoshida H, Imaizumi T, Takamatsu S, Zimmerman GA, McIntyre TM, Gray PW, Prescott SM (- 2) Ref: J Clinical Investigation, 97:2784, 1996 : PubMed ESTHER: Stafforini_1996_J.Clin.Invest_97_2784 PubMedSearch: Stafforini 1996 J.Clin.Invest 97 2784 PubMedID: 8675689 Gene_locus related to this paper: human-PLA2G7 Abstract Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders. Title: Anti-inflammatory properties of a platelet-activating factor acetylhydrolase Tjoelker LW, Wilder C, Eberhardt C, Stafforini DM Ref: Nature, 374:549, 1995 : PubMed ESTHER: Tjoelker_1995_Nature_374_549 PubMedSearch: Tjoelker 1995 Nature 374 549 PubMedID: 7700381 Gene_locus related to this paper: bovin-pafa, canfa-pafa, chick-pafa, human-PLA2G7, mouse-pafa Abstract Platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid that activates cells involved in inflammation. The biological activity of PAF depends on its structural features, namely an ether linkage at the sn-1 position and an acetate group at the sn-2 position. The actions of PAF are abolished by hydrolysis of the acetyl residue, a reaction catalysed by PAF acetylhydrolase. There are at least two forms of this enzyme--one intracellular and another that circulates in plasma and is likely to regulate inflammation. Here we report the molecular cloning and characterization of the human plasma PAF acetylhydrolase. The unique sequence contains a Gly-Xaa-Ser-Xaa-Gly motif commonly found in lipases. Recombinant PAF acetylhydrolase has the substrate specificity and lipoprotein association of the native enzyme, and blocks inflammation in vivo: it markedly decreases vascular leakage in pleurisy and paw oedema, suggesting that PAF acetylhydrolase might be a useful therapy for severe acute inflammation. Title: Human plasma platelet-activating factor acetylhydrolase. Association with lipoprotein particles and role in the degradation of platelet-activating factor Stafforini DM, McIntyre TM, Carter ME, Prescott SM Ref: Journal of Biological Chemistry, 262:4215, 1987 : PubMed ESTHER: Stafforini_1987_J.Biol.Chem_262_4215 PubMedSearch: Stafforini 1987 J.Biol.Chem 262 4215 PubMedID: 3549727 Abstract Platelet-activating factor (PAF) is a bioactive phospholipid (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) synthesized by a variety of mammalian cell types. PAF induces hypotension, and activates neutrophils and platelets, among other actions. Removal of the acetyl moiety abolishes biological activity, so this reaction may regulate the concentration of PAF and its physiological effects. We have studied the significance of this reaction, which is catalyzed in vitro by an acetylhydrolase present in mammalian plasma, blood cells, and tissues. We have shown that the plasma PAF-acetylhydrolase is responsible for the degradation of PAF in whole human blood and that alternate pathways for PAF degradation in plasma or blood cells are negligible. Human plasma PAF-acetylhydrolase is associated with low and high density lipoproteins (LDL and HDL with apoE). We have confirmed that the activity is a stable component of these particles by density gradient ultracentrifugation, chromatography on heparin-agarose, and immunoprecipitation. The LDL-associated activity accounts for most or all of the PAF degradation that occurs in plasma ex vivo, while the HDL-associated activity contributes little to this process. However, the two activities likely are due to a single protein since the HDL- and LDL-associated PAF-acetylhydrolase activities can transfer from one lipoprotein to the other. These transfer processes are pH-dependent and specific, since they only occur from LDL to a well characterized subclass of HDL (apoE-containing HDL) and vice versa. We discuss the equilibrium between the two particles and the role that this process may have in vivo. | |||||||
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