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      Hyperleptinemia Is Not Responsible for Decreased Paraoxonase Activity in Hemodialysis Patients

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          Abstract

          Background: Exogenous leptin markedly decreased plasma paraoxonase (PON1) activity in rats. Hyperleptinemia and decreased PON1 activity have previously been demonstrated in uremia. Therefore, we investigated the relationship between leptin level and PON1 activity in hemodialysis (HD) patients. Methods: Leptin and PON1 were determined in 40 HD patients and 40 age-matched controls with similar body mass index (BMI). Results: Leptin was higher (p < 0.001) and PON1 activity was lower (p < 0.001) in HD patients than in controls. PON1 and PON1/HDL ratio was higher in HD patients with BMI >25 kg/m<sup>2</sup> than in HD patients with BMI <25 kg/m<sup>2</sup>. It was not due to a difference in frequency of high activity phenotype of PON1 among subgroups of HD patients. There was no similar difference in controls. Spearman analysis showed a significant correlation between leptin and PON1 activity (p < 0.02), BMI (p < 0.001), triglyceride (TG) (p < 0.03), and Kt/V (–0.323, p < 0.03), but multiparametric regression analysis did not reveal it. PON1 activity depended on BMI in both models. In controls, leptin correlated with BMI (p < 0.001) and TG (p < 0.002) but not PON1 activity. A slight decrease in leptin concentration and PON1 activity during HD was observed. Conclusion: Our results suggest the role of other pathophysiological conditions besides hyperleptinemia resulting in decreased PON1 activity in HD patients.

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          Most cited references 14

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          Association of morbid obesity and weight change over time with cardiovascular survival in hemodialysis population.

          In maintenance hemodialysis (MHD) outpatients, a reverse epidemiology is described, ie, baseline obesity appears paradoxically associated with improved survival. However, the association between changes in weight over time and prospective mortality is not known. Using time-dependent Cox models and adjusting for changes in laboratory values over time, the relation of quarterly-varying 3-month averaged body mass index (BMI) to all-cause and cardiovascular mortality was examined in a 2-year cohort of 54,535 MHD patients from virtually all DaVita dialysis clinics in the United States. Patients, aged 61.7 +/- 15.5 (SD) years, included 54% men and 45% with diabetes. Time-dependent unadjusted and multivariate-adjusted models, based on quarterly-averaged BMI controlled for case-mix and available time-varying laboratory surrogates of nutritional status, were calculated in 11 categories of BMI. Obesity, including morbid obesity, was associated with better survival and reduced cardiovascular death, even after accounting for changes in BMI and laboratory values over time. Survival advantages of obesity were maintained for dichotomized BMI cutoff values of 25, 30, and 35 kg/m2 across almost all strata of age, race, sex, dialysis dose, protein intake, and serum albumin level. Examining the regression slope of change in weight over time, progressively worsening weight loss was associated with poor survival, whereas weight gain showed a tendency toward decreased cardiovascular death. Weight gain and both baseline and time-varying obesity may be associated with reduced cardiovascular mortality in MHD patients independent of laboratory surrogates of nutritional status and their changes over time. Morbidly obese patients have the lowest mortality. Clinical trials need to verify these observational findings.
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            Glycation impairs high-density lipoprotein function.

            To examine the effects of incubation of high-density lipoprotein (HDL) under hyperglycaemic conditions on several functions of HDL in vitro. Human HDL (5 mg protein) was incubated for 1 week at 37 degrees C in the presence or absence of 25 mmol/l glucose. Additional samples of human HDL were incubated in butylated hydroxytoluene to control for oxidation. High-density lipoprotein incubated for 1 week in 25 mmol/l glucose had significant increases in the glycation product, fructoselysine and in the advanced glycation end product, N epsilon-(carboxymethyl)-lysine. High-density lipoprotein apolipoprotein AI and AII concentrations were not altered but glycated HDL had a 65% reduction in paraoxonase enzymatic activity. Glycated HDL did not inhibit monocyte adhesion to human aortic endothelial cells in response to oxidised low-density lipoprotein in vitro (43 +/- 4 monocytes bound vs 21 +/- 2 monocytes for control HDL, p < 0.0001). Hepatic lipase-mediated non-esterified fatty acid release from HDL lipids was enhanced in glycated HDL compared with control HDL (25 +/- 1 vs 16 +/- 1 nmol non-esterified fatty acid hydrolysed/min, respectively, p < 0.0001). Direct glycation of purified paraoxonase protein by incubation in 25 mmol/l glucose caused a 40% reduction in enzymatic activity. This glycated paraoxonase did not inhibit monocyte adhesion to human aortic endothelial cells in vitro (68 +/- 3 monocytes vs 49 +/- 2 monocytes bound for control paraoxonase, respectively, p < 0.001). We also measured a 40% reduction in paraoxonase activity in patients with Type II (non-insulin-dependent) diabetes mellitus and documented coronary artery disease compared with non-diabetic subjects, p < 0.0001. Alterations in function of HDL caused by exposure to hyperglycaemic conditions could contribute to the accelerated atherosclerosis observed in Type II diabetes.
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              Leptin decreases plasma paraoxonase 1 (PON1) activity and induces oxidative stress: the possible novel mechanism for proatherogenic effect of chronic hyperleptinemia.

               J. Beltowski (2003)
              Obesity is an important risk factor of atherosclerosis; however, the mechanism of proatherogenic effect of obesity is not definitely established. Recent studies suggest an important role of leptin in obesity associated complications. We investigated the effect of chronic hyperleptinemia on two antioxidant enzymes contained in plasma lipoproteins: paraoxonase 1 (PON1) and platelet activating factor-acetylhydrolase (PAF-AH). The study was performed on three groups of male Wistar rats: (1) control, fed ad libitum, (2) leptin treated, receiving leptin (0.25 mg/kg twice daily s.c. for 7 days), (3) pair-fed, in which food intake was identical as in leptin-treated animals. PON1 activity toward paraoxon, phenyl acetate, gamma-decanolactone and homogentisic acid lactone was lower in leptin-treated than in control group by 30.4, 30.8, 34.5 and 62%, respectively. Leptin increased plasma concentration and urinary excretion of isoprostanes by 46.4 and 49.2%, respectively. Leptin treatment had no effect on plasma lipid profile and glucose level. Plasma leptin was 208.8% higher in leptin-treated and 51.5% lower in pair-fed than in control group. These data indicate that hyperleptinemia induced by exogenous leptin administration markedly decreases plasma PON1 activity and induces oxidative stress. These mechanisms may be involved in atherogenesis in hyperleptinemic obese individuals.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2006
                June 2006
                13 March 2006
                : 103
                : 3
                : c114-c120
                Affiliations
                Divisions of aNephrology and bMetabolism, 1st Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
                Article
                92020 Nephron Clin Pract 2006;103:c114–c120
                10.1159/000092020
                16534235
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 6, References: 22, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/92020
                Categories
                Original Paper

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