Elsevier

Atherosclerosis

Volume 214, Issue 1, January 2011, Pages 20-36
Atherosclerosis

Review
The three-gene paraoxonase family: Physiologic roles, actions and regulation

https://doi.org/10.1016/j.atherosclerosis.2010.08.076Get rights and content

Abstract

The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that share considerable structural homology and are located adjacently on chromosome 7 in humans. By far the most-studied member is PON1, a high-density lipoprotein-associated esterase/lactonase, also endowed with the capacity to hydrolyze organophosphates, but all the three proteins prevent oxidative stress and fight inflammation. They therefore seem central to a wide variety of human illnesses, including atherosclerosis, diabetes mellitus, mental disorders and inflammatory bowel disease. The major goal of this review is to highlight the regulation of each of the paraoxonase components by diverse nutritional molecules and pharmacological agents as well as a number of pathophysiological events, such as oxidative stress and inflammation. Considerable and detailed cell-based studies and animal model experiments have been provided to allow a thorough scrutiny of PON modulation, which will increase our understanding and ability to target these genes in order to efficiently increase their transcriptional activity and decrease the risks of developing different disorders.

Introduction

The paraoxonase (PON) gene family contains three different members (PON1, PON2 and PON3), and exhibits antioxidative properties principally in the blood circulation. Recent interests have been directed towards a better comprehension of the functions of PON2 and PON3, but PON1 remains by far the most studied of the three enzymes.

PON1 is a calcium-dependent esterase that was first described for its capacity to hydrolyze organophosphates and pesticides, including paraoxon, which inspired the name of the three enzymes. PON1 is a 43–45 kDa glycoprotein, expressed in a variety of tissues [1], but it is mainly synthesized by the liver and circulates within high-density lipoprotein (HDL) particles [2]. It has been the focus of more intense research activities, because of its evident capacity to protect low-density lipoproteins (LDL) against oxidative stress, reduce macrophage foam cell formation and prevent atherosclerosis development [3]. PON1 gene polymorphisms have been associated with various human diseases, including coronary heart disease [4], Parkinson's disease [5], type 2 diabetes [6] and inflammatory bowel disease [7].

Despite increasing interest in PON2, there is still little information about its functions and characteristics. Although this member of the PON family does not associate with HDL particles in the circulation, it has also been involved in the reduction of oxidative stress and protection against atherosclerosis [8]. PON2 is expressed in nearly all human tissues, including the lungs, liver, heart and intestine [9]. In vascular cells, PON2 was found to be a cell-based enzyme and appeared in two glycosylated isoforms of approximately 40–43 kDa [10]. PON2 gene polymorphisms have been implicated in a variety of human disorders, such as cardiovascular diseases [11], [12], type 2 diabetes [13], [14] and inflammatory bowel disease [15].

PON3, the third member of the multigene family, is similar to PON1 in terms of expression, function and location. Both recombinant human PON1 and PON3 show the capacity to delay LDL oxidation in vitro, with PON1 being more effective than PON3 in this respect [16]. Few data are available for the moment on PON3 polymorphisms and the effects of these variants on human diseases are still unknown [17].

All three PONs seem to be important players in the maintenance of a low oxidative state in the blood circulation and, therefore, the prevention of atherosclerosis. Associations of their polymorphisms with various human diseases show a potential implication of these enzymes in other organs. Of note, PON1 gene polymorphisms have been shown to account for more than 60% of the interindividual variation in enzyme concentration and activity but the three PONs have shown to be modulated by various nutritional and pharmacological molecules and some pathophysiological events such as inflammation and oxidative stress. The purpose of this review is to summarize and update of the major functions attributed to PONs, as well as the nutritional, physiological and pharmacological influences of PON expression and activity in relation to disease. Identifying lifestyle modifications that favor PON expression and activity could have a major impact on atherosclerosis and many other oxidative stress-related diseases. In addition, the discovery of pharmacological products that modulate PONs could be of major clinical importance.

Section snippets

Physiological roles of PON1

PON1 was first studied for its capacity to detoxify organophosphate compounds [18], but the current paper will focus primarily on its antioxidative and anti-inflammatory properties as well as on the potential pathophysiological implications of its modulation.

HDLs are the most powerful independent negative predictors of cardiovascular events. The protective effects of HDLs have first been attributed to their capacity to promote cellular cholesterol efflux from peripheral cells and deliver it to

Physiological roles of PON2

Less information is available regarding the specific functions and regulation of PON2. However, like PON1, it has been implicated in oxidative stress, inflammation and quorum-sensing regulation. Its antioxidative properties may be related to atherosclerosis prevention, although PON2 protein is not detectable in HDL particles. However, PON2 is expressed in nearly all human tissues with a primary localization in the plasma membrane, which suggests functions that are distinct from those reported

Physiological roles of PON3

The biological functions of PON3 were clarified with the pioneer work of Draganov et al. in 2000 [181]. Characterization of rabbit PON3 was carried out following its purification and it interestingly co-purified with PON1 and apo A-I, both known components of HDL, indicating the location of PON3 within HDL particles. Substrate specificity was found to be quite different, as PON3 had no paraoxonase activity and very limited arylesterase activity, but was endowed with a much greater lactonase

Conclusions

PONs (1, 2 and 3) are still relatively newly identified antioxidant enzymes and much more work needs to be done in order to fully elucidate their physiological functions as well as understand their modulation and their implications for human health. PON1, 2 and 3 can all prevent atherosclerosis and control oxidative stress in the blood circulation. Oxidised lipids have shown to be potential substrates for PONs, which could explain their beneficial implication in oxidative stress and

Acknowledgments

This study was supported by the Crohn's and Colitis Foundation of Canada, the JA deSève Research Chair in Nutrition (EL) and the Fonds de la Recherche en Santé du Québec (LPP). The authors thank Mrs Schohraya Spahis for her technical assistance.

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