Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model.

Shih, Diana M.; Gu, Lin; Hama, Susan; Xia, Yu‐Rong; Navab, Mohamad; Fogelman, Alan M.; Lusis, Aldons J.

doi:10.1172/jci118589

Cited by 228 publications

(135 citation statements)

References 42 publications

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“…It has recently been established that the PON content of HDL is a major determinant of the antioxidant capacity of the lipoprotein. 5,7,8 Our results suggest that this antioxidant function of HDL is, at least in part, genetically determined.…”

Section: Discussionmentioning

confidence: 67%

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Promoter Polymorphisms of Human Paraoxonase PON1 Gene and Serum Paraoxonase Activities and Concentrations

Leviev

James

2000

ATVB

288

206

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Abstract-Paraoxonase (PON) is a serum enzyme with a wide species distribution. It protects lipoproteins from toxic oxidative modifications and is an antiatherogenic mechanism of major potential. Activity levels of PON are major determinants of the protective function; consequently, factors that influence PON levels are of particular relevance. The present study has identified 3 polymorphisms in the promoter region of the human PON1 gene. Cell transfection studies have revealed their variable impact on promoter activity, with up to 2-fold differences in reporter gene expression. Genotyping studies have established that the polymorphisms are frequent in the population, a finding that is consistent with a major impact on PON concentrations. The physiological relevance of the polymorphisms was underlined by showing that they are associated with highly significant differences in serum concentrations and activities of PON.

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Section: Discussionmentioning

confidence: 67%

“…[3][4][5][6] In particular, these data have demonstrated that the PON content of HDL is a major determinant of the antioxidant function and, consequently, the anti-inflammatory capacity of the lipoprotein. 2,7,8 Factors that influence PON levels are thus of major consideration for the efficacy of its protective function.…”

mentioning

confidence: 99%

Promoter Polymorphisms of Human Paraoxonase PON1 Gene and Serum Paraoxonase Activities and Concentrations

Leviev

James

2000

ATVB

288

206

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“…Several in vitro studies have shown a direct correlation between variations in PON1 activity and the capacity to prevent LDL oxidation (1,2,16). These observations are corroborated by in vivo studies where serum PON1 levels correlate inversely with levels of lipoprotein oxidation (17) and lesion formation (4,5,18). Thus PON1 concentration is an important determinant of the anti-oxidant capacity of HDL.…”

Section: Paraoxonase-1 (Pon1)mentioning

confidence: 64%

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

Deakin

Leviev

Gomaraschi

et al. 2002

Journal of Biological Chemistry

216

186

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Paraoxonase-1 (PON1) is a high density lipoprotein (HDL)-associated serum enzyme that protects low density lipoproteins from oxidative modifications. There is a relative lack of information on mechanisms implicated in PON1 release from cells. The present study focused on a model derived from stable transfection of CHO cells, to avoid co-secretion of apolipoprotein (apo) A-I and lipids, which could lead to formation of HDL-like complexes. Our results indicate that, in the absence of an appropriate acceptor, little PON1 is released. The results designate HDL as the predominant, physiological acceptor, whose efficiency is influenced by size and composition. Neither lipid-poor apoA-I or apoA-II nor low density lipoproteins could substitute for HDL. Protein-free phospholipid complexes promoted PON1 release. However, the presence of both apolipoprotein and phospholipid were necessary to promote release and stabilize the enzyme. Immunofluorescence studies demonstrated that PON1 was inserted into the external membrane of CHO cells, where it was enzymatically active. Accumulation of PON1 in the cell membrane was not influenced by the ability of the cell to co-secrete of apoA-I. Release appeared to involve desorption by HDL; human and reconstituted HDL promoted PON1 release in a saturable, high affinity manner (apparent affinity 1.59 ؎ 0.3 g of HDL protein/ml). Studies with PON1-transfected hepatocytes (HuH-7) revealed comparable structural features with the peptide located in a punctate pattern at the external membrane and enzymatically active. We hypothesize that release of PON1 involves a docking process whereby HDL transiently associate with the cell membrane and remove the peptide from the external membrane. The secretory process may be of importance for assuring the correct lipoprotein destination of PON1 and thus its functional efficiency. Paraoxonase-1 (PON1)1 is a high density lipoprotein (HDL)-associated serum enzyme that protects low density lipoproteins (LDL) from oxidative modifications. In vitro studies have demonstrated the capacity of PON1 to prevent LDL (and HDL) oxidation by a variety of pro-oxidant factors, including cellinduced LDL oxidation (1, 2). Complementary studies have shown that the anti-oxidant activity of PON1 prevents LDL from acquiring a number of pathological characteristics associated with the atherosclerotic process, notably monocyte mobilization and gene activation (3). The PON1 knockout mouse model confirmed that absence of serum PON1 activity increases the level of lipoprotein oxidation, renders LDL more susceptible to oxidation, decreases the anti-oxidant capacity of HDL and leads to more extensive atheroma formation (4, 5). In man, we first demonstrated that PON1 was an independent, genetic risk factor for coronary disease (6, 7). This has been confirmed independently (8 -11), although not consistently (12,13). In subsequent studies we have shown that PON1 promoter polymorphisms, which affect promoter activity and serum PON1 concentrations (14), are also independent risk factors for...

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“…This reaction suppresses atherogenesis, and it protects lipoprotein particles from chemically reactive phospholipids. Genetic deletion of PON1 activity in mice creates animals that are susceptible to organophosphate intoxication and, importantly, demonstrate an increased propensity to form atherosclerotic lesions when placed on a high fat diet or an apoE knock-out background (7,40,41). Conversely, transgenic mice with increased levels of circulating PON1 are less susceptible to developing atherosclerosis (42,43), as are mice expressing PAF acetylhydrolase as a transgene (44).…”

Section: Genetic Ablation Of Paf Acetylhydrolase Shows Pon1 Has No Romentioning

confidence: 99%

Platelet-activating Factor Acetylhydrolase, and Not Paraoxonase-1, Is the Oxidized Phospholipid Hydrolase of High Density Lipoprotein Particles

Marathe¹,

Zimmerman²,

McIntyre³

2003

Journal of Biological Chemistry

165

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Paraoxonase-1 (PON1), an high density lipoprotein (HDL)-associated organophosphate triesterase, suppresses atherosclerosis in an unknown way. Purified PON1 protects lipoprotein particles from oxidative modification and hydrolyzes pro-atherogenic oxidized phospholipids and the inflammatory mediator plateletactivating factor (PAF). We find human PON1 acted as a phospholipase A 2 but not as a phospholipase C or D through cleavage of phosphodiester bonds as expected. PON1 requires divalent cations, but EDTA did not block the phospholipase A 2 activity of PON1. In contrast, a serine esterase inhibitor abolished phospholipase activity even though PON1 has no active-site serine residues. PAF acetylhydrolase, an oxidized phospholipid phospholipase A 2 , is a serine esterase associated with specific HDL particles. Western blotting did not reveal detectable amounts of PAF acetylhydrolase in PON1 preparations, although very low amounts of PAF acetylhydrolase might still account for PON1 phospholipase A 2 activity. We revised the standard PON1 purification by first depleting HDL of PAF acetylhydrolase to find PON1 purified in this way no longer hydrolyzed oxidized phospholipids or PAF. Serum from a donor with an inactivating mutation in the PAF acetylhydrolase gene did not hydrolyze oxidized phospholipids or PAF, yet displayed full paraoxonase activity. We conclude that PAF acetylhydrolase is the sole phospholipase A 2 of HDL and that PON1 has no phospholipase activity toward PAF or pro-atherogenic oxidized phospholipids. Paraoxonase-1 (PON1)1 catalyzes the hydrolysis of organophosphorous triesters and aryl carboxyl esters; it is of interest because of its hydrolysis of paraoxon (a metabolite of the insecticide parathion) and neurotoxins such as sarin and diisopro-

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Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model.

Cited by 228 publications

References 42 publications

Promoter Polymorphisms of Human Paraoxonase PON1 Gene and Serum Paraoxonase Activities and Concentrations

Promoter Polymorphisms of Human Paraoxonase PON1 Gene and Serum Paraoxonase Activities and Concentrations

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

Platelet-activating Factor Acetylhydrolase, and Not Paraoxonase-1, Is the Oxidized Phospholipid Hydrolase of High Density Lipoprotein Particles

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