Elsevier

Biochemical Pharmacology

Volume 66, Issue 11, 1 December 2003, Pages 2069-2073
Biochemical Pharmacology

Commentary
Effect of hypolipidemic drugs on lipoprotein-associated platelet activating factor acetylhydrolase: Implication for atherosclerosis

https://doi.org/10.1016/S0006-2952(03)00559-8Get rights and content

Abstract

Human plasma platelet activating factor acetylhydrolase (PAF-AH) is an enzyme associated mainly with the apolipoprotein B (apoB)-containing lipoproteins and primarily with low-density lipoprotein (LDL). A small proportion of enzyme activity is also associated with high-density lipoprotein (HDL). PAF-AH activity is essential for the metabolism of PAF and oxidized phospholipids, i.e. bioactive lipids that are involved in the pathophysiology of atherosclerosis. Thus, PAF-AH may play a significant role in atherogenesis. Accumulating data indicate that PAF-AH associated with HDL particles plays a predominantly antiatherogenic role. By contrast, the role of LDL-associated PAF-AH remains controversial. Dyslipidemia induces a significant increase in total plasma PAF-AH activity and alters the enzyme distribution between proatherogenic apoB- and antiatherogenic apo AI-containing lipoproteins by increasing the PAF-AH activity associated with apoB-containing lipoproteins. The decreased rate of LDL removal from the circulation and the abnormal catabolism of triglyceride-rich lipoproteins play important roles in these abnormalities. Atorvastatin or fenofibrate therapy can restore, at least partially, the dyslipidemia-induced alterations in plasma PAF-AH by increasing the ratio of HDL-PAF-AH to plasma PAF-AH (or to LDL-cholesterol) levels, which may represent an important antiatherogenic effect of these hypolipidemic drugs.

Introduction

PAF-AH is an enzyme that exhibits an α/β hydrolase conformation and has broad substrate specificity towards lipid esters containing short acyl chains. Among the various activities, the Ca2+-independent phospholipase A2 activity of PAF-AH has been principally studied. Indeed, PAF-AH has marked preference for phospholipids with short chain moieties at the sn-2 position and, in addition to the potent proinflammatory lipid mediator PAF, it can hydrolyze proinflammatory and proatherogenic oxidized phospholipids [1].

In normolipidemic human plasma PAF-AH is associated mainly with the apoB-containing lipoproteins and primarily with LDL. A small proportion of circulating enzyme activity (less than 20%) is associated with HDL. Within these lipoprotein pools, the enzyme preferentially associates with small-dense LDL and with the very high-density lipoprotein-1 (VHDL-1) subfraction, alternatively denoted as HDL-3c [2]. Among LDL subspecies, the PAF-AH activity in normolipidemic plasma is positively correlated only with the enzyme activity associated with dense LDL subfractions, thus further supporting the preferential association of PAF-AH with small-dense LDL particles [3]. The distribution of PAF-AH between LDL and HDL can be influenced by the presence of lipoprotein (a) (Lp(a)) when plasma levels of this lipoprotein exceed 30 mg/dL [4]. It has been shown that Lp(a) contains several-fold greater PAF-AH activity compared with LDL when assayed at equimolar protein concentrations [4], [5].

The primary sources of circulating PAF-AH constitute cells of hematopoietic origin and primarily macrophages [6], [7]. Although PAF-AH in plasma is associated with lipoproteins, their existence in plasma is not required for the enzyme activity. Since the cells of hematopoietic origin do not secrete lipoproteins, it seems that secretion of PAF-AH occurs independently of the secretion of lipoprotein particles; the enzyme subsequently associates with these particles in plasma. Consistent with this hypothesis, PAF-AH activity in plasma of individuals with HDL deficiency (Tangier disease) is higher than that of normal subjects [8], whereas individuals with abetalipoproteinemia have normal or slightly subnormal PAF-AH activity [9]. However, our recent studies have demonstrated that the lipoprotein metabolism as well as the lipoprotein plasma levels significantly influences the plasma PAF-AH activity. In this brief report, we present our resent results on the effect of hypolipidemic drugs on the plasma- and lipoprotein-associated PAF-AH activity in the most common types of dyslipidemia, primary hypercholesterolemia, combined hyperlipidemia, and primary hypertriglyceridemia.

Section snippets

Effect of hypolipidemic drugs on PAF-AH activity in patients with primary hypercholesterolemia

Patients with primary hypercholesterolemia (Type IIA dyslipidemia) exhibit an elevation of total plasma- and LDL-associated PAF-AH activity whereas the HDL-associated enzyme activity (HDL-PAF-AH) is not significantly altered. The plasma enzyme activity is positively correlated with total plasma cholesterol, LDL-cholesterol, as well as apoB levels. The increase in the LDL-PAF-AH concerns the increase in enzyme activity associated with all LDL particles, i.e. the large, intermediate, and

Effect of hypolipidemic drugs on PAF-AH activity in patients with combined hyperlipidemia

Similar to the results obtained for the total plasma- and LDL-associated PAF-AH activity in patients with primary hypercholesterolemia, are those obtained in patients with combined hyperlipidemia (Type IIB dyslipidemia). However, a significant increase in the subfraction of triglyceride-rich very low-density lipoprotein+intermediate-density lipoprotein (VLDL+IDL), in parallel to the increase in LDL-associated enzyme activity, is also observed in this patient group. This increase contributes to

Effect of fenofibrate on PAF-AH activity in patients with primary hypertriglyceridemia

Like in the other types of dyslipidemia, patients with primary hypertriglyceridemia (Type IV dyslipidemia) exhibit significantly higher plasma PAF-AH activity than normolipidemic volunteers. However, in contrast to Types IIA and IIB dyslipidemic patients, the increased levels of triglyceride-rich lipoproteins may play a key role in this elevation. Indeed, the enzyme activity associated with LDL as well as with individual LDL subspecies, including small-dense LDL, is not altered in primary

Plasma PAF-AH in atherosclerosis: the role of hypolipidemic therapy

PAF-AH may play a significant role in atherogenesis and cardiovascular disease due to its role in the metabolism of bioactive lipids, such as PAF and oxidized phospholipids [1]. However, the role of this enzyme in atherosclerotic disease remains a subject of controversy. Data from the WOSCOPS trial suggest that plasma levels of PAF-AH mass, which mainly reflects the LDL-associated enzyme, represent an independent risk factor for coronary artery disease [18]. In contrast, results from the

Conclusion

Dyslipidemia induces a significant increase in total plasma PAF-AH activity and alters the enzyme distribution between proatherogenic apoB- and antiatherogenic apo AI-containing lipoproteins. The decreased rate of LDL removal from the circulation and the abnormal catabolism of triglyceride-rich lipoproteins play important roles in these abnormalities. Accumulating data indicate that PAF-AH activity associated with HDL particles plays a predominantly antiatherogenic role. By contrast, the role

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