Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles

Mackness, Mike; Mackness, Bharti

doi:10.1016/j.gene.2015.04.088

Cited by 250 publications

(251 citation statements)

References 142 publications

(157 reference statements)

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“…Much of the biological activity of HDL is due to its protein content, with it carrying >50 distinct proteins with known functions in inflammation, oxidation, protease inhibition, complement regulation, and innate immunity (44). Paraoxonase 1 (PON1), an HDL-associated lipolactonase, contributes to HDL antioxidant and anti-inflammatory functions by preventing both LDL and HDL particles from oxidation (45). PON1-deficient mice are more sensitive to lipoprotein oxidation and the development of atherosclerosis (39,46).…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

Millar

Duclos

Blesso

2017

Advances in Nutrition

141

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Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their welldocumented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function. Based on preclinical studies that used cell culture and rodent models, it appears that many flavonoids (e.g., anthocyanidins, flavonols, and flavone subclasses) influence RCT and HDL function beyond simple HDL cholesterol concentration by regulating cellular cholesterol efflux from macrophages and hepatic paraoxonase 1 expression and activity. In clinical studies, dietary anthocyanin intake is associated with beneficial changes in serum biomarkers related to HDL function in a variety of human populations (e.g., in those who are hyperlipidemic, hypertensive, or diabetic), including increased HDL cholesterol concentration, as well as HDL antioxidant and cholesterol efflux capacities. However, clinical research on HDL functionality is lacking for some flavonoid subclasses (e.g., flavanols, flavones, flavanones, and isoflavones). Although there has been a tremendous effort to develop HDL-targeted drug therapies, more research is warranted on how the intake of foods or specific nutrients affects HDL function. Adv Nutr 2017;8:226-39.

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Section: Introductionmentioning

confidence: 99%

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

Millar

Duclos

Blesso

2017

Advances in Nutrition

141

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“…MPO level and its role in oxidative stress and inflammation has been implicated in the pathophysiology of cardiovascular diseases such as coronary artery disease [6] . Human paraoxonase-1 (PON1) is a calcium-dependent lactonase that is produced by the liver and almost exclusively associated with HDL [7] . Although hydrolysis of homocysteine thiolactone might represent a major physiologic function of PON1 [8] , several further substrates have been described including other lactones [9] , organophosphates and lipid peroxides [7] .…”

Section: Introductionmentioning

confidence: 99%

HDL subfraction distribution and HDL function in untreated dyslipidemic patients

Harangi¹,

Szentpéteri²,

Nádró³

et al. 2017

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Aim:The protective role of high-density lipoprotein (HDL) against atherosclerosis is well known. However, both structural and functional changes of the HDL particles may affect its protective efficacy. Increased levels of HDL-associated myeloperoxidase (MPO) and decreased HDL-linked paraoxonase-1 (PON1) activity have been reported in dyslipidemic patients. Some changes in HDL subfraction distributions were also studied previously, but data on structural and functional changes in dyslipidemia are not complete. Therefore, the authors aimed to evaluate these qualitative and quantitative markers of HDL in dyslipidemic patients and healthy control subjects. Methods: Anthropometric parameters, serum levels of lipoproteins and MPO, as well as PON1 activities were investigated in 81 untreated dyslipidemic patients and in 32 healthy gender-matched controls. Additionally, HDL subfractions were detected by an electrophoretic method on polyacrylamide gel (Lipoprint). Results: Significantly higher glucose, hemoglobin A1c, total cholesterol, low-density lipoprotein-cholesterol, triglyceride, lipoprotein(a), apolipoprotein B, C-reactive protein, and MPO levels were found in patients compared to the healthy subjects. There were no significant differences in PON1 paraoxonase and arylesterase activities between the two study groups, but MPO/PON1 ratio was significantly higher in patients. There was a shift towards the smaller HDL subfractions, but only the intermediate HDL ratio was significantly lower in patients compared to controls. Conclusion:The results highlight the importance of HDL-associated pro-and antioxidant enzymes suggesting the possible clinical benefit of MPO/PON1 calculation and confirm that quantification of HDL-C level alone provides limited data regarding HDL's cardioprotective effect. Calculation of MPO/PON1 ratio may be a useful cardiovascular marker in dyslipidemia. Key words:High-density lipoprotein, subfraction, paraoxonase, myeloperoxidase, dyslipidemia ABSTRACTArticle history:

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“…PON1 has also been shown to stimulate HDL-dependent nitric oxide (NO) production by endothelial nitric-oxide synthase (10,(32)(33)(34). PON1 possesses both esterase and lactonase catalytic activities in vitro but has unclear substrate(s) in vivo (35). A role for PON1 protection from atherosclerosis in vivo has been supported by studies showing PON1 knock-out mice have accelerated atherosclerosis (36), and human PON1 transgenic mice demonstrate both protection from atherosclerosis and reduced indices of systemic oxidative stress (31,37).…”

mentioning

confidence: 99%

Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction

Gu¹,

Huang²,

Levison³

et al. 2016

Journal of Biological Chemistry

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However, specific residues on PON1 involved in the HDL-PON1 interaction remain unclear. Unambiguous identification of protein residues involved in docking interactions to lipid surfaces poses considerable methodological challenges. Here we describe a new strategy that uses a novel synthetic photoactivatable and click chemistry-taggable phospholipid probe, which, when incorporated into HDL, was used to identify amino acid residues on PON1 that directly interact with the lipoprotein phospholipid surface. Several specific PON1 residues (Leu-9, Tyr-185, and Tyr-293) were identified through covalent crosslinks with the lipid probes using affinity isolation coupled to liquid chromatography with on-line tandem mass spectrometry. Based upon the crystal structure for PON1, the identified residues are all localized in relatively close proximity on the surface of PON1, defining a domain that binds to the HDL lipid surface. Site-specific mutagenesis of the identified PON1 residues (Leu-9, Tyr-185, and Tyr-293), coupled with functional studies, reveals their importance in PON1 binding to HDL and both PON1 catalytic activity and stability. Specifically, the residues identified on PON1 provide important structural insights into the PON1-HDL interaction. More generally, the new photoactivatable and affinity-tagged lipid probe developed herein should prove to be a valuable tool for identifying contact sites supporting protein interactions with lipid interfaces such as found on cell membranes or lipoproteins.

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Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles

Cited by 250 publications

References 142 publications

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

HDL subfraction distribution and HDL function in untreated dyslipidemic patients

Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction

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