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

Nutrition, Metabolism & Cardiovascular Diseases (2012) 22, 88e94

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/nmcd

REVIEW

Effect of dietary lipids on paraoxonase-1 activity and gene expression G. Ferretti a,*, T. Bacchetti b a

Dipartimento di Scienze Cliniche Sperimentali e Odontostomatologiche, Universita` Politecnica delle Marche, 60131 Ancona, Italy b Dipartimento di Scienze della Vita e dell’Ambiente, Universita` Politecnica delle Marche, 60131 Ancona, Italy Received 16 March 2011; received in revised form 11 August 2011; accepted 23 August 2011

KEYWORDS Dietary lipids; Fatty acids; High density lipoproteins (HDL); Nutrigenomics; Paraoxonase-1 (PON1)

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. ª 2011 Elsevier B.V. All rights reserved.

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].

* Corresponding author. Dipartimento di Scienze Cliniche Sperimentali e Odontostomatologiche, Universita ` Politecnica delle Marche, Via Ranieri 65, 60131 Ancona, Italy. Tel.: þ39 71 220 4968; fax: þ39 71 220 4673. E-mail addresses: [email protected] (G. Ferretti), [email protected] (T. Bacchetti). 0939-4753/$ - see front matter ª 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2011.08.011

Dietary lipids and paraoxonase-1 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 [3e6]. 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 [7e9] 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 ApoAIcontaining 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

Table 1

Functional roles of PON1.

- Protective effect against lipid peroxidation of HDL, LDL and biological membranes - Detoxify a toxic metabolite of homocysteine, homocysteine-thiolactone which damages protein by homocysteinylation of lysine residues. - Protective effect exerted against postprandial oxidative stress - Inhibition of cholesterol biosynthesis in macrophages - Stimulation of cholesterol efflux from macrophages - Modulation of lipid metabolism of human adipose tissue

89 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 [3e6]. 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 homocysteinethiolactone (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].

Effect of dietary lipids on paraoxonase-1 The effect of dietary lipids on PON1 activity has been mainly investigated in animal models. Table 2 (as supplementary file) summarizes the results obtained. In addition to paraoxon (paraoxonase activity) the substrates used have been respectively: phenylacetate for arylesterase activity and dihydrocumarin and thiobutyl-butyrolactone for lactonase activity. High fat, high cholesterol diet- A decrease in PON1 hepatic expression and serum enzyme activity has been demonstrated in atherosclerosis-susceptible mice (C57BL/ 6J) [27,28] and other animal models fed for several weeks with high fat diet [29,30]. A decrease in serum PON1 activity and liver mRNA has been observed also after few days of atherogenic diet treatment [31]. A decrease of PON1 activity after high fat diet was demonstrated in other animal models [32,33].

90

G. Ferretti, T. Bacchetti

Figure 1 Hypothetical mechanisms by which HDL-PON1 protects against lipid peroxidation of lipoproteins. Lipid peroxidation products of phospholipids and cholesteryl ester in oxidized lipoproteins or membranes are the proposed physiological substrates of PON1. PON1 could hydrolyze oxidized phospholipids to lysophosphatidylcholine (LPC) and inactive compounds. Rosenblat et al. (2006) have proposed that oxidized lipids with hydroxyl groups at the 50 -position or related derivatives, could be lactonized by PON1 to yield LPC and the respective d-valerolactone products. The latter can be hydrolyzed by PON1 to yield the corresponding 5hydroxycarboxylic acid. In agreement with Aviram et al. (2000), cholesteryl ester-hydroperoxides could be substrates for peroxidase-like activity of PON1, with consequent formation of cholesteryl ester hydroxides.

Saturated fatty acids- No significant modification in plasma activity was observed in Male SpragueeDawley rats after a diet enriched in saturated fatty acids [34]. Monounsaturated fatty acids- An increase in PON1 activity was observed in different animal models fed with high oleic diet (treatment from 20 days to 2 months) [34e36]. An increase in PON1 activity associated with monounsaturated fatty acids intake was observed also in human subjects [36e38]. In particular, Tomas et al. [37] have reported that the beneficial effect of oleic acid intake on PON1 activity realized at a higher extent in subjects carrying the R allele of the PON1e192 polymorphism. In agreement with these results, it has been demonstrated that PON1 increased its function in R carriers following the monounsaturated-enriched diet [39]. A postprandial increase in PON1 activity after a Mediterraneanlike meal containing a high amount of monounsaturated

(61% of fat) has also been demonstrated [40]. No significant changes have been reported by other authors [14,41]. Polyunsaturated fatty acids- A significant decrease in postprandial serum PON1 activity associated with an increase of susceptibility of serum to lipid peroxidation has been demonstrated after fish oil supplementation [14]. Similar results were obtained after long-term administration of fish oil in rats [34,42]. The effect has been confirmed in humans [41]. The role of polyunsaturated fatty acids (PUFAs) deserves of future studies; in fact although they are considered protective against atherosclerosis, longchain PUFAs are highly susceptible to lipid peroxidation and this may negatively affect PON1 activity [34]. Trans fatty acids- Trans fatty acids (TFA) are formed during the industrial hydrogenation of vegetable oils for food manufacturing or by biohydrogenation in the rumens of cows and sheep. TFA intake is associated with increased

Dietary lipids and paraoxonase-1 risk of cardiovascular disease. Replacing saturated fat with trans in the diet of healthy subjects resulted in decreased serum PON1 activity [43]. An increase of PON1 activity has been observed in Golden Syrian hamsters fed with diet enriched with conjugated linoleic acid (CLA) [44], the results were not confirmed using a different experimental model [45,47]. Oxidized fatty acids- A postprandial decrease in PON1 activity induced by dietary fats containing hydroperoxides has been demonstrated [46], whereas the consumption of a meal rich in thermally stressed olive oil has been shown to significantly increase serum PON1 levels in women [47].

Molecular mechanisms The comparison of the results of the aforementioned studies shows that the amount, the composition of dietary fatty acids and the length of the dietary treatment modulate paraoxonase-1. Alterations in PON1 synthesis, secretion, stability and its association to HDL or direct inactivation of the PON1, explain at least in part the dietary induced changes of PON1. The molecular mechanisms that appear to be involved are summarized in Figs. 2e4. Effect of fatty acids and lipid hydroperoxides on PON1 synthesis The correlation between the decrease in PON1 activity and levels of hepatic PON1 mRNA reported after treatment with atherogenic diet for several weeks (8e14 weeks) [27e30], suggests that alterations in serum PON1 activity primarily reflects modifications of hepatic PON1 synthesis. Gene expression of PON1 and of other factors involved in HDL synthesis, such as reverse cholesterol

91 transporter ABCA1, are modulated through cell receptormediated signaling pathways and nuclear receptors (such as peroxisome-proliferetor-activated receptors, PPARs). Either free radicals and lipid peroxidation products appear to be involved in the decrease of expression of PPARd and hepatic PON1 [48] (Fig. 2). The relationship between hepatic PON1 mRNA and levels of markers of lipid peroxidation and expression of inflammatory genes observed after high fat diet (HFD) diet, suggests that modulation of PON1 is part of inflammatory response elicited by lipid peroxides [27]. Obesity is associated to inflammation and oxidative stress [49]. Therefore the decrease in PON1 activity and the increase of level of markers of lipid peroxidation in blood observed previously in obese animal models [33] and in human subjects [15] could be due to the increased synthesis of ROS and pro-inflammatory cytokines (TNF-a, IL-1, and IL-6) from adipose tissue and liver [49]. However other mechanisms could be involved in the decrease of PON1 activity after HFD. In fact a genderrelated decrease in PON1 activity in absence of an increase in pro-inflammatory markers after HFD containing similar amount of saturated and monounsaturated fatty acids, has been demonstrated [30]. The involvement of oxidative stress has been suggested to play a role also in the decrease of serum PON1 activity and of hepatic PON1 gene expression after high PUFA diet omega 3 diet in rats [42]. Effect of HDL on PON1 stability. As aforementioned, PON1 is a lipid-dependent enzyme whose secretion by liver, stability and stimulation of its activity are modulated by HDL [50]. Dietary induced changes in HDL lipid composition and fluidity have been previously demonstrated [51]. HDL have a mean biologic half-life (4e6 days) longer with respect to

Figure 2 Effect of high-fat ehigh cholesterol diet on paraoxonase-1. High fat diet is associated with inflammatory response and increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) by blood and liver cells (1). There is a consequent increase of markers of lipid peroxidation in blood and in hepatic tissue (2) with macrophage infiltration and propagation of oxidative damage and inflammation (3)- In hepatic cells lipid peroxidation products could modulate PPARd gene expression (4). The decrease in PPARd could be associated with: inhibition of gene expression of PON1(5) and of ATP-binding cassette transporter (ABCA1) (6). The consequent lower HDL synthesis (7) and PON1 secretion (8) can results in a lower PON1 activity in serum (9). ([increase; Ydecrease).

92

G. Ferretti, T. Bacchetti

HDL physico-chemical properties (polarity, fluidity, order)

Lipid-apoprotein interactions DIETARY LIPIDS

LIPID COMPOSITION OF HDL

HDL FUNCTIONS (PON1 activity, reverse cholesterol transport, interaction with cell receptors) Apoprotein conformation at HDL surface

Susceptibility to lipid peroxidation

Figure 3 Effect of dietary lipids on lipid composition and physico-chemical properties of HDL and consequences on HDL functions.

other lipoproteins; therefore we may expect that dietary induced compositional changes of HDL may reflect in modifications of its liver secretion and binding of PON1 to the surface of HDL (Fig. 3). It has to be stressed that HDL fatty acid composition modulates also its susceptibility to lipid peroxidation and previous studies have shown that HDL oxidized in vitro have a reduced capacity to stabilize/ improve activity of secreted PON1 [52]. The positive effect of oleic acid supplementation observed in aforementioned studies might in part be due to the protective effect of

oleylated phospholipids on oxidative inactivation of PON1 as well as on its stability [53]. As far as concerns the molecular mechanisms involved in the alterations of PON1 by oxidized dietary lipids, it has been established that lipid peroxides can be absorbed by the small intestine, transported in chylomicrons to the liver and than assembled in VLDL, LDL and HDL [54]. The decrease in PON1 activity after meals rich in oxidized lipids is in agreement with in vitro studies where PON1 was found to be inactivated by oxidized lipids [9] (Fig. 4).

Figure 4 Effect of intake of thermally stressed fatty acids on paraoxonase-1 activity. Oxidized dietary lipids are absorbed by the small intestine (1) and are secreted as oxidized chylomicrons (ox-CM) and transported to the liver (2). Oxidized lipids can be assembled in oxidized VLDL (ox-VLDL) (3). Oxidized HDL (ox-HDL) results from metabolism of ox-CM and ox-VLDL via lipoprotein lipase (LPL) (4). Oxidized HDL show a reduced PON1 activity due to the inhibitory effect exerted by lipid peroxidation products. Moreover ox-HDL have a lower ability to stabilize/improve activity of secreted PON1 (5). ([increase; Ydecrease).

Dietary lipids and paraoxonase-1

Conclusions The roles of PON1 in the modulation of lipid metabolism is a research area under intense investigation. The review shows evidence that dietary lipids and lipid peroxidation products modulate PON1 gene expression and activity. Diet rich in oleic acid exerts a protective effect on PON1 activity. On the contrary a decrease PON1 activity has been demonstrated after an high fat intake and by trans fatty acids. Most of the studies of dietary fatty acids have been investigated using paraoxon and phenylacetate as substrates. Fewer studies have used other substrates such as dihydrocumarin and thiobutyl-butyrolactone for lactonase activity. This could represent a limit for the aforementioned studies; however, although paraoxon and phenylacetate are not the physiological substrates of PON1, they have been widely used to investigate PON1 in normal and pathological conditions. To better understand the molecular mechanisms involved in the dietary induced effect on human PON1, future studies should be carried out measuring PON1 quantity and quality designed as status ‘PON1 status’ as proposed by Richter and Furlong [55]. The evaluation of serum levels of ApoA1, ApoJ and HDL and lipid peroxidation products could also be useful indexes to investigate the molecular mechanisms because they are involved in PON1 functions.

Appendix. Supplementary material Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.numecd. 2011.08.011

References [1] Kris-Etherton PM, Yu S, Etherton TD, Morgan R, Moriarty K, Shaffer D. Fatty acids and progression of coronary artery disease. Am J Clin Nutr 1997;65:1088e90. [2] Pe ´gorier JP, LMCa GJ. Control of gene expression by fatty acids. J Nutr 2004;134:2444Se9S. [3] Precourt LP, Amre D, Denis MC, Lavoie JC, Delvin E, Seidman E, et al. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis 2011;214: 20e36. [4] Furlong CE, Suzuki SM, Stevens RC, Marsillach J, Richter RJ, Jarvik GP, et al. Human PON1, a biomarker of risk of disease and exposure. Chem Biol Interact 2010;187:355e61. [5] Camps J, Marsillach J, Joven J. Measurement of serum paraoxonase-1 activity in the evaluation of liver function. World J Gastroenterol 2009;15:1929e33. [6] Costa LG, Giordano G, Furlong CE. Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: the hunt goes on. Biochem Pharmacol 2011;81: 337e44. [7] Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, et al. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 1995;96:2882e91. [8] Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res 2000;41:1495e508.

93 [9] Aviram M, Rosenblat M, Bisgaier CL, Newton RS, PrimoParmo SL, La Du BN. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest 1998;101: 1581e90. [10] Jakubowski H. Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J Biol Chem 2000;275: 3957e62. [11] Rozenberg O, Shih DM, Aviram M. Human serum paraoxonase 1 decreases macrophage cholesterol biosynthesis: possible role for its phospholipase-A2-like activity and lysophosphatidylcholine formation. Arterioscler Thromb Vasc Biol 2003;23: 461e7. [12] Rosenblat M, Vaya J, Shih D, Aviram M. Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: a possible role for lysophosphatidylcholine. Atherosclerosis 2005;179:69e77. [13] Zafiropoulos A, Linardakis M, Jansen EH, Tsatsakis AM, Kafatos A, Tzanakakis GN. Paraoxonase 1 R/Q alleles are associated with differential accumulation of saturated versus 20:5n3 fatty acid in human adipose tissue. J Lipid Res 2010;51: 1991e2000. [14] Fuhrman B, Volkova N, Aviram M. Postprandial serum triacylglycerols and oxidative stress in mice after consumption of fish oil, soy oil or olive oil: possible role for paraoxonase-1 triacylglycerol lipase-like activity. Nutrition 2006;22:922e30. [15] Ferretti G, Bacchetti T, Masciangelo S, Bicchiega V. HDL-paraoxonase and membrane lipid peroxidation: a comparison between healthy and obese subjects. Obes (Silver Spring) 2010;18:1079e84. [16] Ferretti G, Bacchetti T, Busni D, Rabini RA, Curatola G. Protective effect of paraoxonase activity in high-density lipoproteins against erythrocyte membranes peroxidation: a comparison between healthy subjects and type 1 diabetic patients. J Clin Endocrinol Metab 2004;89:2957e62. [17] Paragh G, Balla P, Katona E, Seres I, Egerhazi A, Degrell I. Serum paraoxonase activity changes in patients with Alzheimer’s disease and vascular dementia. Eur Arch Psychiatry Clin Neurosci 2002;252:63e7. [18] Sorenson RC, Bisgaier CL, Aviram M, Hsu C, Billecke S, La Du BN. Human serum Paraoxonase/Arylesterase’s retained hydrophobic N-terminal leader sequence associates with HDLs by binding phospholipids: apolipoprotein A-I stabilizes activity. Arterioscler Thromb Vasc Biol 1999;19:2214e25. [19] Harel M, Brumshtein B, Meged R, Dvir H, Ravelli RB, McCarthy A, et al. 3-D structure of serum paraoxonase 1 sheds light on its activity, stability, solubility and crystallizability. Arh Hig Rada Toksikol 2007;58:347e53. [20] Deakin S, Leviev I, Gomaraschi M, Calabresi L, Franceschini G, James RW. Enzymatically active paraoxonase-1 is located at the external membrane of producing cells and released by a high affinity, saturable, desorption mechanism. J Biol Chem 2002;277:4301e8. [21] Gaidukov L, Rosenblat M, Aviram M, Tawfik DS. The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux. J Lipid Res 2006;47:2492e502. [22] Cherki M, Berrougui H, Isabelle M, Cloutier M, Koumbadinga GA, Khalil A. Effect of PON1 polymorphism on HDL antioxidant potential is blunted with aging. Exp Gerontol 2007;42:815e24. [23] Kuremoto K, Watanabe Y, Ohmura H, Shimada K, Mokuno H, Daida H. R/R genotype of human paraoxonase (PON1) is more protective against lipoprotein oxidation and coronary artery disease in Japanese subjects. J Atheroscler Thromb 2003;10: 85e92.

94 [24] Tsimikas S, Miller YI. Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des 2011; 17:27e37. [25] Rosenblat M, Gaidukov L, Khersonsky O, Vaya J, Oren R, Tawfik DS, et al. The catalytic histidine dyad of high density lipoprotein-associated serum paraoxonase-1 (PON1) is essential for PON1-mediated inhibition of low density lipoprotein oxidation and stimulation of macrophage cholesterol efflux. J Biol Chem 2006;281:7657e65. [26] Ferretti G, Bacchetti T, Masciangelo S, Bicchiega V. Effect of homocysteinylation on high density lipoprotein physicochemical properties. Chem Phys Lipids 2010;163:228e35. [27] Shih DM, Gu L, Hama S, Xia YR, Navab M, Fogelman AM, et al. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest 1996;97:1630e9. [28] Navab M, Hama-Levy S, Van Lenten BJ, Fonarow GC, Cardinez CJ, Castellani LW, et al. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest 1997;99:2005e19. [29] Mackness M, Boullier A, Hennuyer N, Mackness B, Hall M, Tailleux A, et al. Paraoxonase activity is reduced by a proatherosclerotic diet in rabbits. Biochem Biophys Res Commun 2000;269:232e6. [30] Thomas-Moya E, Gianotti M, Proenza AM, Llado I. Paraoxonase 1 response to a high-fat diet: gender differences in the factors involved. Mol Med 2007;13:203e9. [31] Hedrick CC, Hassan K, Hough GP, Yoo JH, Simzar S, Quinto CR, et al. Short-term feeding of atherogenic diet to mice results in reduction of HDL and paraoxonase that may be mediated by an immune mechanism. Arterioscler Thromb Vasc Biol 2000; 20:1946e52. [32] Durak I, Ozbek H, Devrim E, Karagenc N, Erguder IB. Effects of cholesterol supplementation on antioxidant enzyme activities in rat hepatic tissues: possible implications of hepatic paraoxonase in atherogenesis. Nutr Metab Cardiovasc Dis 2004;14: 211e4. [33] Thomas-Moya E, Gomez-Perez Y, Fiol M, Gianotti M, Llado I, Proenza AM. Gender related differences in paraoxonase 1 response to high-fat diet-induced oxidative stress. Obes (Silver Spring) 2008;16:2232e8. [34] Kudchodkar BJ, Lacko AG, Dory L, Fungwe TV. Dietary fat modulates serum paraoxonase 1 activity in rats. J Nutr 2000; 130:2427e33. [35] Rosenblat M, Volkova N, Coleman R, Almagor Y, Aviram M. Antiatherogenicity of extra virgin olive oil and its enrichment with green tea polyphenols in the atherosclerotic apolipoprotein-E-deficient mice: enhanced macrophage cholesterol efflux. J Nutr Biochem 2008;19:514e23. [36] Efrat M, Rosenblat M, Mahmood S, Vaya J, Aviram M. Di-oleoyl phosphatidylcholine (PC-18:1) stimulates paraoxonase 1 (PON1) enzymatic and biological activities: in vitro and in vivo studies. Atherosclerosis 2009;202:461e9. [37] Tomas M, Senti M, Elosua R, Vila J, Sala J, Masia R, et al. Interaction between the Gln-Arg 192 variants of the paraoxonase gene and oleic acid intake as a determinant of highdensity lipoprotein cholesterol and paraoxonase activity. Eur J Pharmacol 2001;432:121e8. [38] Cherki M, Derouiche A, Drissi A, El Messal M, Bamou Y, IdrissiOuadghiri A, et al. Consumption of argan oil may have an antiatherogenic effect by improving paraoxonase activities and antioxidant status: intervention study in healthy men. Nutr Metab Cardiovasc Dis 2005;15:352e60. [39] Delgado-Lista J, Perez-Jimenez F, Gavilan E, Marin C, Fuentes F, Fernandez-Puebla RA, et al. A carbohydrate-rich diet reduces LDL size in QQ homozygotes for the Gln 192Arg

G. Ferretti, T. Bacchetti

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

polymorphism of the paraoxonase 1 gene. Lipids 2005;40: 471e6. Blum S, Aviram M, Ben-Amotz A, Levy Y. Effect of a Mediterranean meal on postprandial carotenoids, paraoxonase activity and C-reactive protein levels. Ann Nutr Metab 2006;50:20e4. Freese R, Alfthan G, Jauhiainen M, Basu S, Erlund I, Salminen I, et al. High intakes of vegetables, berries, and apples combined with a high intake of linoleic or oleic acid only slightly affect markers of lipid peroxidation and lipoprotein metabolism in healthy subjects. Am J Clin Nutr 2002;76:950e60. Varatharajalu R, Garige M, Leckey LC, Gong M, Lakshman MR. Betaine protects chronic alcohol and omega-3 PUFA-mediated down-regulations of PON1 gene, serum PON1 and homocysteine thiolactonase activities with restoration of liver GSH. Alcohol Clin Exp Res 2010;34:424e31. de Roos NM, Schouten EG, Scheek LM, van Tol A, Katan MB. Replacement of dietary saturated fat with trans fat reduces serum paraoxonase activity in healthy men and women. Metabolism 2002;51:1534e7. Valeille K, Ferezou J, Amsler G, Quignard-Boulange A, Parquet M, Gripois D, et al. A cis-9, trans-11-conjugated linoleic acid-rich oil reduces the outcome of atherogenic process in hyperlipidemic hamster. Am J Physiol Heart Circ Physiol 2005;289:H652e9. Arbones-Mainar JM, Navarro MA, Acin S, Guzman MA, Arnal C, Surra JC, et al. Trans-10, cis-12- and cis-9, trans-11conjugated linoleic acid isomers selectively modify HDLapolipoprotein composition in apolipoprotein E knockout mice. J Nutr 2006;136:353e9. Sutherland WH, Walker RJ, de Jong SA, van Rij AM, Phillips V, Walker HL. Reduced postprandial serum paraoxonase activity after a meal rich in used cooking fat. Arterioscler Thromb Vasc Biol 1999;19:1340e7. Wallace AJ, Sutherland WH, Mann JI, Williams SM. The effect of meals rich in thermally stressed olive and safflower oils on postprandial serum paraoxonase activity in patients with diabetes. Eur J Clin Nutr 2001;55:951e8. Marsillach J, Camps J, Ferre N, Beltran R, Rull A, Mackness B, et al. Paraoxonase-1 is related to inflammation, fibrosis and PPAR delta in experimental liver disease. BMC Gastroenterol 2009;9:3. Svegliati-Baroni G, Candelaresi C, Saccomanno S, Ferretti G, Bachetti T, Marzioni M, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol 2006;169:846e60. Deakin SP, James RW. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci (Lond) 2004;107:435e47. Shepherd J, Packard CJ, Patsch JR, Gotto Jr AM, Taunton OD. Effects of dietary polyunsaturated and saturated fat on the properties of high density lipoproteins and the metabolism of apolipoprotein A-I. J Clin Invest 1978;61:1582e92. Deakin S, Moren X, James RW. HDL oxidation compromises its influence on paraoxonase-1 secretion and its capacity to modulate enzyme activity. Arterioscler Thromb Vasc Biol 2007;27:1146e52. Nguyen SD, Sok DE. Beneficial effect of oleoylated lipids on paraoxonase 1: protection against oxidative inactivation and stabilization. Biochem J 2003;375:275e85. Ahotupa M, Suomela JP, Vuorimaa T, Vasankari T. Lipoproteinspecific transport of circulating lipid peroxides. Ann Med 2010; 42:521e9. Richter RJ, Furlong CE. Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenetics 1999;9:745e53.