ReviewLipoprotein lipase and atherosclerosis
Introduction
Lipoprotein lipase (LPL) is a key enzyme in hydrolysis of chylomicron and very low density lipoprotein (VLDL) triglyceride (TG). The LPL gene is about 35 kb in length, contains ten exons, and is mapped to chromosome 8p22 [1]. The released fatty acids are taken up mainly by the heart, skeletal muscle and adipose tissue. These organs are the principal sites of LPL synthesis, but in the heart it occurs mainly not in the cardiac myocytes but rather in interstitial ‘mesenchymal cells’ [2]. This was documented by in situ hybridization, which showed that the highest concentration of LPL mRNA is seen in these cells [3]. Apart from its lipolytic activity, LPL in cell cultures acts also as a cholesteryl ester transferase into cells, a process that is not linked to the catalytic activity of the enzyme and is dissociated from the uptake of the protein moiety of lipoproteins [4], [5]. The LPL-mediated selective uptake of lipoprotein cholesteryl ester occurs also in vivo, as exemplified by uptake of cholesteryl linoleyl ether by the lactating mammary gland after injection of labeled chylomicrons [6].
The transferase activity of LPL induced the enrichment of aortic smooth muscle cells (SMC) exposed to cholesteryl oleate, and these results suggested that, in the aortic wall, LPL could play a role in cholesteryl ester accretion in SMC that occurs during atherogenesis [7]. Within the wall of the atherosclerotic artery, LPL is derived mainly from macrophages and SMC [8], [9], [10], and studies in cell culture have demonstrated its regulation by various cytokines [11]. A revival in the interest in the role LPL plays in atherosclerosis occurred in the mid nineties and the highlights of this field of research had been admirably reviewed [11], [12], [13], [14], [15]. In this review we shall focus on the evaluation of the balance between the pro and antiatherogenic properties of LPL in experimental animals as well as in humans. The frequent mutations in the LPL gene, which have been recently described in various populations, will provide the basis for the discussion of the putative link between LPL and coronary heart disease (CHD).
Section snippets
Proatherogenic role of macrophage LPL
Zilversmit was the first to propose that chylomicron and VLDL remnants formed by endothelial LPL may contribute to the development of atherosclerosis [16]. While the above mentioned mechanism stressed the putative role of endothelial surface bound LPL, subsequent research was directed also towards elucidation of the involvement of macrophage LPL in this process. Thus, fetal hepatic cells obtained from donors homozygous for LPL−/− or LPL+/+ were injected into irradiated mice, and atherosclerosis
Role of LPL in lipoprotein bridging and selective CE uptake
An important facet of potential proatherogenic activity of LPL is linked to its capacity to enhance binding of lipoproteins to cellular receptors, such as LRP [26], and to heparan sulfate on cell surfaces and extracellular matrix [27], [28]. This subject was dealt with extensively in a recent review [15]; we shall discuss the aspect of LPL mediated selective cellular uptake of cholesteryl ester from lipoproteins. The synthesis of an unhydrolyzable analog of cholesteryl ester, namely cholesteryl
Antiatherogenic effects of LPL
The first studies on the atheroprotective effect of plasma LPL were performed on mice overexpressing hLPL [42], [43]. In the LDL-R−/− mice overexpressing hLPL, plasma cholesterol and TG levels were lower by 40 and 90%, respectively, than in LDL-R−/− controls [42]. Atherosclerosis was found to be reduced 18-fold in the LPL overexpressing mice, which was most likely due to the lower plasma lipid levels [42]. In apoE−/− mice overexpressing hLPL, fed an atherogenic diet, plasma total cholesterol
Regulation of LPL by PPAR's, RXR and LXR
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which, when heterodimerized with the retinoic acid receptor (RXR), bind to a specific peroxisome-proliferator response element, and regulate expression of target genes active in lipid metabolism [47]; this element has been identified in the hLPL promoter [48]. Cultured adult rat cardiomyocytes were treated with synthetic or natural PPAR-α ligands and after 16 h, cellular and heparin releasable LPL
LPL mutations and CHD
During the last decade, interest was reawakened in the relationship between LPL and atherosclerosis in humans. Three common LPL mutations—N291S, D9N and S447X, that occur at a relatively high frequency, enabled investigators to look for the link between LPL genetic variation and CHD. The D9N mutation is due to a change of aspartate residue to asparagine, the N291S is due to an asparagine to serine change, and the S447X is due to a premature stop codon, with the loss of serine and lysine
Concluding remarks
The data obtained from studies in transgenic animals demonstrate the involvement of LPL in atherosclerosis. The atheroprotective role of plasma LPL is well documented, and the mode of operation is linked to its catalytic activity, resulting in decrease in plasma TG and increase in HDL-C. On the other hand, the mechanism by which macrophage LPL enhances atherosclerosis is more complex as it involves also the noncatalytic activity of the enzyme on lipoproteins, such as bridging and selective
Addendum
During the time this manuscript was under review, three reviews on LPL were published emphasizing the renewed interest in this subject [83], [84], [85].
Acknowledgements
We do acknowledge the invaluable comments and suggesions of Professor Y. Friedlander, especially with regard to the section dealing with mutations. Our thanks are extended to N. Kellman for her indefatigable help and patience in the preparation of the manuscript for publication.
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