Paraoxonase-1 (PON-1) genotype and activity and <i>in vivo</i> oxidized plasma low-density lipoprotein in Type II diabetes

Sampson, Mike; S, Braschi; Willis, Gavin; Astley, Siân

doi:10.1042/cs20050089

Cited by 42 publications

(25 citation statements)

References 58 publications

(71 reference statements)

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“…In this study, we found a negative correlation between PON1 activity and circulating oxidized LDL concentration in the control population, but we were unable to find such an association in type 2 diabetic or CHD populations. This is contrary to previous findings in diabetes (16,17). The reasons for these discrepancies are not obvious but could be caused by differences in study populations, number of subjects studied, or diabetes control.…”

Section: Discussioncontrasting

confidence: 56%

“…PON1 is low in patients with diabetes (13)(14)(15), leading to dysfunctional HDL with impaired antioxidant capacity (15). In type 2 diabetes, there is an inverse relationship between PON1 activity and circulating oxidized LDL levels (16,17), indicative of the major role of PON1 in retarding LDL oxidation. We have recently shown that adenovirus-mediated overexpression of human PON1 in a mouse model of metabolic syndrome significantly inhibited atherosclerosis development by reducing oxidized LDL in both plasma and the artery wall (18).…”

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confidence: 99%

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Defective Metabolism of Oxidized Phospholipid by HDL From People With Type 2 Diabetes

Mastorikou

Mackness

2006

Diabetes

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HDL protects against atherosclerosis development. Defective functioning of HDL in type 2 diabetes may be one cause of increased cardiovascular disease associated with type 2 diabetes. HDL modulates LDL oxidation through the action of paraoxonase-1 (PON1), which is one of the major mechanisms by which HDL is antiatherogenic. We have compared the ability of HDL from people with type 2 diabetes (n ‫؍‬ 36) with no coronary heart disease (CHD) to metabolize oxidized palmitoyl arachidonyl phosphatidylcholine (ox-PAPC), a major product of LDL oxidation and a PON1 substrate, with that of HDL isolated from healthy control subjects (n ‫؍‬ 19) and people with CHD but no diabetes (n ‫؍‬ 37). HDL from people with type 2 diabetes metabolized 11% less ox-PAPC, and HDL from people with CHD metabolized 6% less, compared with HDL from control subjects (both P < 0.01). The ability of HDL from control and type 2 diabetic subjects containing the PON1-192RR alloform to metabolize ox-PAPC was significantly reduced compared with PON1-192QQ or QR genotypes (P < 0.05). The defective ability of HDL to metabolize ox-PAPC was reflected in a significant increase in circulating plasma oxidized LDL concentration in the two patient groups (37 ؎ 5, 53 ؎ 7, and 65 ؎ 7 mmol/l for control, CHD, and type 2 diabetic subjects, respectively; P < 0.001), with PON1-192RR genotype carriers having the highest concentrations. In the control group, there was a significant negative correlation between serum PON1 activity and oxidized LDL concentration (r ‫؍‬ 0.856, P < 0.001); however, this correlation was not evident in the patient groups. HDL from type 2 diabetic subjects without CHD had a decreased ability to metabolize oxidized phospholipids, which could lead to increased susceptibility to develop cardiovascular disease. Diabetes 55: 3099 -3103, 2006 T he oxidation of LDL in the artery wall is believed to be the primary event leading to the initiation and progression of atherosclerosis (1,2). HDL, on the other hand, is protective against the development of atherosclerosis (3,4). The primary protective effect of HDL was believed to be its pivotal role in reverse-cholesterol transport; however, HDL also has antioxidative, anti-inflammatory, and antithrombotic properties (5).HDL-associated paraoxonase-1 (PON1) is primarily responsible for the antioxidative properties of HDL in retarding the oxidation of LDL (6 -10). By modulating the oxidation of LDL, PON1 abolishes the oxidized LDLstimulated induction of monocyte-chemotactic protein-1 (MCP-1) production by endothelial cells, thereby preventing monocyte-endothelial cell interaction in one of the earliest processes of atherosclerosis (11,12). PON1 is low in patients with diabetes (13-15), leading to dysfunctional HDL with impaired antioxidant capacity (15). In type 2 diabetes, there is an inverse relationship between PON1 activity and circulating oxidized LDL levels (16,17), indicative of the major role of PON1 in retarding LDL oxidation. We have recently shown that adenovirus-mediated overexpression of hu...

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Section: Discussioncontrasting

confidence: 56%

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confidence: 99%

Defective Metabolism of Oxidized Phospholipid by HDL From People With Type 2 Diabetes

Mastorikou

Mackness

2006

Diabetes

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“…5 It has also been shown that plasma ox-LDL levels correlate with human serum paraoxonase in patients with type 2 diabetes. 35,36 Because the assay for ox-LDL in blood is based on a mouse monoclonal antibody, ox-LDL cannot be measured directly in mouse blood. Previously, the titer of autoantibodies against MDA-modified LDL has been used as a proxy for ox-LDL in mice.…”

Section: Effect Of Pon1 Gene Transfer On Plasma Ox-ldl Levelsmentioning

confidence: 99%

Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome

Mackness

Quarck

Verreth

et al. 2006

ATVB

159

104

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Background-The metabolic syndrome is typified by obesity, dyslipidemia, diabetes, hypertension, increased oxidative stress, and accelerated atherosclerosis. Paraoxonase1 (PON1), a high-density lipoprotein (HDL)-associated antioxidant enzyme that prevents the oxidation of low-density lipoprotein (LDL), is low in the metabolic syndrome. Methods and Results-We used adenovirus-mediated PON1 gene transfer (AdPON1) to overexpress human PON1 in mice with combined leptin and LDL receptor deficiency, a model of metabolic syndrome. PON1 activity, plasma lipids, the titer of autoantibodies against malondialdehyde (MDA)-modified LDL, and atherosclerosis in AdPON1 mice were compared with these in mice that received a control recombinant adenovirus (AdRR5). PON1 activity was increased 4.4-fold (PϽ0.001) in AdPON1 mice (Nϭ12), whereas in AdRR5 mice (Nϭ11) activity did not change. Expressing human PON1 significantly reduced the total plaque volume, the volume of plaque macrophages, and of plaqueassociated oxidized LDL. It increased the percentage of smooth muscle cells in the plaques. Expressing human PON1 lowered the titer of autoantibodies against MDA-modified LDL, a proxy for oxidized LDL in mice. It had no overall effect on plasma total cholesterol and triglycerides, as evidenced by the similar area under the curves, and on the HDL distribution profile. Conclusion-Our data suggest that in this mouse model of metabolic syndrome, expressing human PON1 inhibited the development of atherosclerosis, probably by reducing the amount of oxidized LDL in plasma and in the plaque, thereby preventing its proatherogenic effects. Adenovirus-mediated gene transfer of human PON1 may be a potential and useful tool to prevent/retard atherosclerosis in humans. Key Words: atherosclerosis Ⅲ metabolic syndrome Ⅲ oxidized LDL Ⅲ paraoxonase-1 I nsulin resistance is now receiving increasing attention not only as a precursor to type 2 diabetes but also as a predictor of increased risk of cardiovascular disease. 1 Fat distributed in the abdominal region is a risk factor for type 2 diabetes and cardiovascular disease and is associated closely with insulin resistance. 2 In the metabolic syndrome, increased oxidative stress associated with insulin resistance appears to be a major cause of accelerated atherosclerosis. 3,4 Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that, among many other functions, metabolizes pro-inflammatory lipids formed during the oxidation of low-density lipoprotein (LDL) and is therefore potentially anti-atherogenic. 5 PON1 destroys LDL lipid peroxides on LDL and in arteries in vitro and ex vivo. [5][6][7] In PON1 knockout mice, an atherogenic diet causes significantly greater atherosclerosis than in wild-type littermates, whereas overexpressing human PON1 in mouse models of atherosclerosis reduces macrophage oxidative stress and inhibits the development of atherosclerosis. 8,9 The extent to which macrophages infiltrate the artery wall also appears to be dependent on the activity of PON1. 10 PON1 inhi...

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“…(14,15) This may be due to the inactivation of paraoxonase via glycation, a decrease in its gene expression or the inhibition of high-density lipoprotein synthesis or secretion, which is reported to be associated with serum paraoxonase. (14,16) In the present study, we did not observe any significant changes in paraoxonase activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of vitamin A, C and E, or omega-3 fatty acid supplementation on the level of paraoxonase and arylesterase activity in streptozotocin-induced diabetic rats: an investigation of activities in plasma, and heart and liver homogenates

Zarei

Fakher

Tabei

et al. 2016

smedj

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INTRODUCTIONThis study was designed and conducted to evaluate the effects of vitamin A, C and E supplementation, and omega-3 fatty acid supplementation on the activity of paraoxonase and arylesterase in an experimental model of diabetes mellitus. METHODSA total of 64 male Sprague Dawley ® rats, each weighing 250 g, were randomly distributed into four groups:(a) normal control; (b) diabetic control; (c) diabetic with vitamin A, C and E supplementation; and (d) diabetic with omega-3 fatty acid supplementation. The animals were anaesthetised after four weeks of intervention, and paraoxonase and arylesterase activity in blood plasma, and liver and heart homogenates were measured. RESULTSArylesterase activity in the heart and liver homogenates was significantly lower in the diabetic control group than in the normal control group (p < 0.01). Vitamin A, C and E supplementation, and omega-3 fatty acid supplementation significantly increased liver arylesterase activity (p < 0.05). No significant change was observed in paraoxonase activity and other investigated factors.CONCLUSION Vitamin A, C and E, or omega-3 fatty acid supplementation were found to increase liver arylesterase activity in streptozotocin-induced diabetic rats. These supplements may be potential agents for the treatment of diabetes mellitus complications.

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Paraoxonase-1 (PON-1) genotype and activity and in vivo oxidized plasma low-density lipoprotein in Type II diabetes

Cited by 42 publications

References 58 publications

Defective Metabolism of Oxidized Phospholipid by HDL From People With Type 2 Diabetes

Defective Metabolism of Oxidized Phospholipid by HDL From People With Type 2 Diabetes

Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome

Effects of vitamin A, C and E, or omega-3 fatty acid supplementation on the level of paraoxonase and arylesterase activity in streptozotocin-induced diabetic rats: an investigation of activities in plasma, and heart and liver homogenates

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