Effect of dietary lipids on paraoxonase-1 activity and gene expression

Abstract

Aims

Aim of the paper was to summarize the literature about the effect of dietary lipids on activity of paraoxonase-1 (PON1), a multifunctional enzyme associated with high density lipoprotein (HDL). PON1 exerts a protective effect against oxidative damage of cells and lipoproteins and modulates the susceptibility of HDL and LDL to atherogenic modifications such as homocysteinylation.

Data synthesis

The present review shows evidence that the amount and the composition of dietary lipids are key factors in the modulation of PON1. The effect of dietary lipids is also modulated by PON1 polymorphisms. The molecular mechanisms involved include an effect on PON1 hepatic synthesis or secretion and/or modification of PON1 interactions with HDL. Changes of PON1 activity could also be related to dietary intake of oxidized lipids that behave as PON1 inhibitors.

Conclusion

Dietary fatty acids by the modulation of PON1 gene expression and activity could constitute an useful approach for the prevention of human diseases associated with oxidative damage.

Introduction

Dietary fatty acids regulate plasma lipid metabolism modifying the risk of cardiovascular and inflammatory diseases [1]. Fatty acids, in addition to their roles as structural components of biological membranes and lipoproteins, modulate signal transduction and gene expression in liver, white adipose tissue and muscle [2].

Aim of the paper is to review the effect of dietary lipids on the HDL- associated enzyme paraoxonase-1 (PON1), one of the three members of PON enzymes family [3], [4], [5], [6]. The interest of the study is supported by the multifunctional roles exerted by PON1. Although the name “paraoxonase” reflects the ability of the enzyme to hydrolyze organophosphates such as paraoxon, PON 1 plays a key role in the antioxidant and anti-inflammatory properties of HDL [7], [8], [9] and detoxifies a toxic metabolite of homocysteine, homocysteine-thiolactone (HTL), which damages protein by homocysteinylation of lysine residues [10]. As summarized in Table 1 other roles have been attributed to PON1 that was shown to inhibit cholesterol biosynthesis [11] and to stimulate cholesterol efflux from macrophages [12]. Furthermore a role in lipid metabolism of human adipose tissue [13] and a protective effect against postprandial oxidative stress has been suggested [14] (Table 1).

A decrease of PON1 activity has been demonstrated in human diseases such as obesity [15], diabetes [16] and neurodegerative diseases [17]. Therefore, dietary induced modulation of PON1 activity and antioxidant role could constitute a useful approach for the prevention of human diseases associated with oxidative damage.

Relationship between polymorphism, structure and functions of PON1. PON 1 has a molecular mass of 43 kDa (355 aminoacids). The aminoterminal methionine residue is removed during secretion and maturation [18]. The crystal structure of PON1 has provided a model for its anchoring onto HDL [19]. In agreement with this model PON1 might be an interfacially activated enzyme [19] stabilized and catalytically activated by ApoA1, the main apoprotein of HDL. A large proportion of PON1 is associated with ApoAI-containing HDL particles, although particles containing ApoAI and ApoAII do exist [20]. A subpopulation of HDL containing ApoJ associated with PON1 has also been evidenced [20]. More than 200 single nucleotide polymorphisms (SNPs) identified in the human PON1 gene account for more than 60% of the interindividual variation in enzyme concentration and activity. The two polymorphisms: leucine(L)/methionine(M) at position 55 and glutamine(Q)/arginine(R) at position 192 and their pathophysiological roles have been recently reviewed [3], [6], [20]. The two isoforms (PON192R and PON192Q) differ in their catalytic activity toward synthetic substrates used to evaluate enzyme activity in vitro: the aminoacid 192 is an important active-site residue of the enzyme and constitutes part of the HDL-anchoring surface [21]. Therefore R/Q isozymes differ in their HDL binding properties and, as a result, in their stability, lactonase activity and macrophage cholesterol efflux [21]. The PON55L isoform is associated with higher serum activity and higher stability and resistance to proteolysis with respect to PON55M [22], furthermore L55 plays a key role in correct packing of the protein [19]. A relationship between PON1 genotypes and the antioxidant activity of HDL has also been demonstrated [23]. Furthermore the significant decrease in HDL antioxidant activity with aging [22] realizes at higher extent in HDL of subjects homozygous for PONQQ and LL genotypes. Despite the several differences in activity and functionality of PON1 isoforms, the association of PON1 polymorphisms with the development of atherosclerosis is not yet resolved [3], [4], [5], [6]. These results may be related to the fact that atherosclerosis is a complex disease that depends on multiple factors, including genetic, environmental and dietary factors.

Antioxidant properties of PON1: physiological substrates. Oxidation of LDL by free radicals or cell enzymes play an important role in the development of atherosclerotic lesion [24]. The biological properties have been related to an increase of lipid peroxidation products that stimulate the production of pro-inflammatory cytokines and induce adhesion of monocytes to endothelial surface [24]. Figure 1 summarizes the possible physiological substrates of PON1 and molecular mechanisms involved in the protective effect against lipid peroxidation of LDL and HDL. Rosenblat et al. proposed a mechanism for hydrolysis of oxidized lipids by PON1 based on the lactonizing (lactone formation) and lactonase (lactone hydrolysis) activities of the enzyme [25]. Other authors have attributed to PON1 a peroxidase activity on cholesteryl ester-hydroperoxides, fatty acids hydroperoxides and hydrogen peroxide (H₂O₂) [9] (Fig. 1). The aforementioned lactonase activity could allow the hydrolysis of a variety of other endogenous lactones such as homocysteine-thiolactone (HTL) [10]. Therefore, PON1 could exert a protective effect against homocysteinylation of LDL and other proteins by detoxifying HTL [26]. Lactonase activity could also mediate stimulation of HDL-mediated macrophage cholesterol efflux [25].