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Lipoproteins Alter the Catalytic Behavior of the Platelet-Activating Proc. Natl. Acad. Sci. USA Vol. 86, pp. 2393-2397, April 1989 Medical Sciences Lipoproteins alter the catalytic behavior of the platelet-activating factor acetylhydrolase in human plasma (inflammation/thrombosis/phospholipases/low density lipoprotein) DIANA M. STAFFORINI, M. ERIC CARTER, GuY A. ZIMMERMAN, THOMAS M. MCINTYRE, AND STEPHEN M. PREscorr Nora Eccles Harrison Cardiovascular Research and Training Institute and Departments of Internal Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112 Communicated by Philip W. Majerus, December 15, 1988 ABSTRACT Platelet-activating factor (PAF) has been im- between the two particles (6). This distribution is interesting plicated as a mediator of inflammation, allergy, shock, and because the two particles do not have a common metabolic thrombosis. A specific degradative enzyme, PAF acetyihydro- pathway, but both are involved in cholesterol homeostasis lase (EC 3.1.1.47), is found in plasma and could regulate the (reviewed in ref. 10). concentration of PAF in blood. In plasma, 70% of the PAF We found (6, 9) that the PAF acetylhydrolase activities in acetylhydrolase is found with low density lipoprotein (LDL), LDL and HDL appear to be the same protein and have and the remainder is in high density lipoprotein (HDL). In identical behavior in an optimized assay with a substrate previous studies we found that with subsaturating concentra- concentration of 80 AtM (i.e., conditions to measure an initial tions ofPAF the activity in LDL seemed to be the relevant one; rate). However, when we examined circumstances that are e.g., depletion of LDL slowed degradation of PAF, while likely to occur in vivo, we found a difference in their behavior removal of HDL accelerated the degradation slightly. We have (6). The t1/2 of PAF was measured in plasma at a concentra- pursued this observation by using plasma from humans with tion ofPAF of either 1 nm or 0.1 AuM and then compared with lipoprotein mutations. In abetalipoproteinemia, all of the PAF the t112 in plasma that had been depleted of LDL, HDL, or acetylhydrolase activity was in HDL, whereas in Tangier both. In all cases the residual activity, as judged by the disease all of the activity was in LDL. In both conditions the optimized assay, was more than enough to ensure that it total activity measured in an optimized assay was normal or would not be the limiting component. The result was that increased. However, when we measured the t1/2 of PAF in removal of LDL significantly prolonged the t1/2, whereas plasma, we found that it was prolonged in subjects with removal ofHDL shortened it. Thus, it appeared that the PAF abetalipoproteinemia compared to normal controls. Con- acetylhydrolase activity in LDL is the physiologically rele- versely, the t1/2 in Tangier plasma was shortened. We next vant one. These findings may be important in human pathol- demonstrated that the PAF acetylhydrolase in HDL was ogy since PAF has been found in blood during allergic recognized by an antibody to the enzyme purified from LDL, reactions (11) and in renal and hepatic disease (12-14). In the establishing that the enzyme in the two particles is the same present study, we have examined these issues further by protein. Finally, we inactivated the PAF acetylhydrolase in using plasma from subjects with mutations in the relevant isolated lipoprotein particles and then reconstituted them with lipoproteins. enzyme from the opposite particle. The reconstituted particles were used to measure the t1/2 of PAF, and we again found that the LDL particle was more efficient. We conclude that the MATERIALS AND METHODS lipoprotein environment of the PAF acetylhydrolase markedly Materials. [acetyl-3H]PAF and [alkyl-3H]PAF were pur- influences its catalytic behavior. This may be important in chased from New England Nuclear. Polyclonal goat antibod- pathophysiology and will complicate attempts to assess the role ies to human apolipoprotein B (apoB) were obtained from of this enzyme in such circumstances. Technicon. Other reagents were from Sigma. The plasma samples from normal subjects were obtained from healthy Platelet-activating factor (PAF) is a phospholipid (1-0-alkyl- volunteers. The samples from three patients with abetali- 2-acetyl-sn-glycero-3-phosphocholine) that activates plate- poproteinemia (15) were provided by Roger Illingworth lets and leukocytes, causes increased vascular permeability, (University of Oregon). Another sample from a patient with and has other effects, all at concentrations as low as 0.1 nM abetalipoproteinemia was supplied by David Wilson (Boston (reviewed in refs. 1 and 2). Mammalian plasma contains an Children's Hospital). This subject, who has not been de- enzyme, PAF acetylhydrolase (1-alkyl-2-acetylglycerophos- scribed in the literature, has typical clinical and laboratory phocholine esterase, 1-alkyl-2-acetyl-sn-glycero-3-phospho- findings. The subject with Tangier disease is a patient ofDana choline acetohydrolase, EC 3.1.1.47), that specifically cata- Wilson (University of Utah), and has typical clinical and lyzes the hydrolysis of the acetyl residue and thereby laboratory manifestations (16). abolishes the bioactivity (3-5). The PAF acetylhydrolase in Assays. PAF acetylhydrolase activity was determined as human plasma was shown by Farr et al. (3) to be associated described (1 unit = 1 Amol/hr) (9). The method for deter- with low density lipoprotein (LDL). We and others have mining the t1/2 of PAF has been described in detail (6). confirmed this finding (6-8), and we have purified the Extractions oflipids used the method of Bligh and Dyer (17), enzyme from LDL to near homogeneity (9). At physiological and thin-layer chromatography separations were performed pH, about 70% of the PAF acetylhydrolase activity is by using solvent system II of Mueller et al. (18). associated with LDL, and the remainder is associated with Analyses of the Lipoprotein Location(s) of the PAF Acetyl- high density lipoprotein (HDL) (6). The activity can exchange hydrolase Activity. The isolation of HDL- and LDL- The publication costs of this article were defrayed in part by page charge Abbreviations: PAF, platelet-activating factor; LDL., low density payment. This article must therefore be hereby marked "advertisement" lipoprotein; HDL, high density lipoprotein; DFP, diisopropyl fluo- in accordance with 18 U.S.C. §1734 solely to indicate this fact. rophosphate; apoB, apolipoprotein B. 2393 Downloaded by guest on September 28, 2021 2394 Medical Sciences: Stafforini et al. Proc. Natl. Acad. Sci. USA 86 (1989) associated PAF acetyihydrolase activities was carried out by excluded the possibility that either HDL or LDL is required ultracentrifugation in KBr gradients as described (6). Frac- for the activity of the acetylhydrolase to be expressed. This tions (1.5 ml) were collected and assayed. Transfer of PAF result also confirms our previous conclusion (6) that the PAF acetylhydrolase from HDL to LDL and from LDL to HDL acetylhydrolase is not a fragment of apoB-100. was carried out by dialysis at alkaline and acidic pH, The distribution of the PAF acetylhydrolase in normal respectively (6). The association of PAF acetylhydrolase plasma is 60-70% in LDL with the remainder in HDL (6). We with apoB was examined by precipitation with anti-apoB. We asked whether the distribution in the lipoprotein disorders incubated 1 1L of plasma from normal or deficient subjects was proportional to the content of the two particles since the with 10 ;LI of goat anti-apoB, in a total volume of 20 /A, for activity can exchange between them (6). We found that the 2 hr at 370C. The antiserum had been previously treated with PAF acetylhydrolase activity was localized only in LDL diisopropyl fluorophosphate (DFP; 10 mM, 60 min at 370C) to and/or HDL (Fig. 1). In the subjects with abetalipoprotein- inactivate the PAF acetylhydrolase present in goat serum. emia (who lack LDL), all of the activity was located at a Excess DFP was removed by overnight dialysis against 50 density almost identical to that ofnormal HDL (Fig. 1A). The mM Tris-HCI (pH 7.5). After the incubation with the anti- minor difference in the densities (Fig. 1, A versus B) was apoB, 30 of protein A-Sepharose 6MB [50:50 suspension observed in each of the four subjects and was reproducible. in 50 mM Tris HCl (pH 7.5)] were added, and the incubations The difference was likely due to the altered composition of were continued for an additional 2 hr at 370C, with rocking. HDL that has been described in abetalipoproteinemia (10). The amount ofPAF acetylhydrolase activity was determined To establish whether this particle was the same as the HDL in the supernatants after removal of the protein A-Sepharose that contains PAF acetylhydrolase in normal plasma, we beads by centrifugation. Control experiments demonstrated performed two experiments. In the first, we examined that control DFP-treated goat serum and DFP-treated anti- whether this particle, like those in normal plasma, could apoB had no effect by themselves on acetylhydrolase activ- donate its acetylhydrolase activity to LDL (6). Plasma from ity. In addition, the enzyme did not interact directly with subjects with abetalipoproteinemia was incubated at pH 9.0 protein A-Sepharose. We have previously shown that the with normal plasma (that had been pretreated with DFP to precipitation of PAF acetylhydrolase activity by this anti- inactivate the endogenous acetylhydrolase). Just as with body is based on the recognition ofthe apolipoprotein and not normal HDL serving as a donor particle, the particle in the enzyme was car- the (6). Heparin-agarose chromatography abetalipoproteinemia plasma served as a donor to LDL (data ried out as previously described (6), except that a step elution not shown). The second piece of evidence that the high was used instead of a gradient. density particle was functionally the same as that in normal Antibody to PAF Acetyihydrolase.
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