Published online before print January 17, 2008, doi: 10.1161/ATVBAHA.107.157891
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Elevated Gamma-Glutamyltransferase Activity and Perturbed Thiol Profile Are Associated With Features of Metabolic Syndrome
From the Unités de Prévention Cardiovasculaire (P.G., C.D., B.H., E.B., X.G.), Service d’Endocrinologie-Métabolisme, Assistance Publique/Hopitaux de Paris, Groupe Hospitalier Pitié-Salpétrière–Université Pierre et Marie Curie; Laboratoire de Biochimie (N.J.), Assistance Publique/Hopitaux de Paris, Groupe Hospitalier Pitié-Salpétrière–Université Pierre et Marie Curie; Dyslipoproteinemia and Atherosclerosis Research Unit (P.G., B.H., A.C., E.B., X.G., M.J.C.), UMRS 551, National Institute for Health and Medical Research (INSERM) and Pierre et Marie Curie University (UPMC–Paris VI); Service de Biochimie Médicale (A.C.), Assistance Publique/Hopitaux de Paris, Groupe Hospitalier Pitié-Salpétrière–Université Pierre et Marie Curie, Paris, France.
Correspondence to Docteur P. Giral, Unités de Prévention Cardiovasculaire-Groupe Hospitalier Pitié-Salpêtrière, 47–83 boulevard de l’hôpital, 75651 Paris Cedex 13, France. E-mail philippe.giral{at}psl.aphp.fr
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Abstract |
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Background— Prospective cohort studies have revealed that plasma
-glutamyltransferase (GGT) activity exhibits a positive association with coronary artery disease. GGT which is equally elevated in metabolic syndrome (MS), is the major regulator of circulating concentrations of thiol compounds derived from glutathione (GSH) cleavage, ie, cysteine and cysteinyl glycine. We compared the circulating thiol profile in a cohort of patients displaying atherogenic dyslipidemia with and without MS. Methods and Results— This cross-sectional study involved 1131 dyslipidemic patients in primary prevention of whom 26% presented with MS. GGT activity and plasma cysteinyl-glycine and cysteine concentrations were higher in MS patients; by contrast, levels of GSH were significantly lower (P<10 to 4 for all comparisons versus patients without MS). We compared patient groups on the basis of the number of MS criteria which were concomitantly present. A progressive decrease in glutathione levels in contrast to a progressive increase in both cysteinyl–glycine and cysteine levels, and GGT activity, was observed as a function of the number of MS components in the overall population (P for trend <10–6).
Conclusion— Dyslipidemic patients exhibiting MS are characterized by elevated GGT activity which is associated with perturbed metabolism of thiol compounds.
We evaluated components of the plasma redox system in dyslipidemic patients with metabolic syndrome as a function of the number of qualifying criteria. Our findings suggest that metabolic syndrome is characterized by elevated GGT activity which is in turn associated with a cascade of abnormalities in the thiol redox system.
Key Words: metabolic syndrome • -glutamyltransferase • glutathione • cysteine • oxidation
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Introduction |
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Recent prospective cohort studies have revealed that plasma gamma glutamyltransferase (GGT) activity exhibits a graded positive association with the severity of coronary artery disease (CAD), and equally with cardiovascular morbidity and mortality.1–2 GGT is central to the extracellular catabolism of glutathione (GSH), a low molecular weight sulfydryl compound which, as a scavenger of oxygen free radicals, plays a key role in protecting against both intracellular and extracellular oxidative stress.3,4 The action of GGT on glutathione results in its cleavage to produce cysteine (cys) and cysteinyl-glycine (Cys-Gly), and as such GGT is the principle regulator of their circulating concentrations.4–5 Cysteine is the most abundant plasma thiol and several reports, including our own, suggest that circulating cysteine levels may be associated with atherosclerosis and CVD.6–7
Our earlier studies demonstrated that the incidence of elevation of circulating hepatic enzymes in a cohort of dyslipidemic patients occurred frequently (27.6%), and in addition revealed that elevation of transaminases and GGT was significantly associated with features of the metabolic syndrome.8 Moreover, metabolic syndrome (MS) is typically associated with a subclinical inflammatory state and oxidative stress.11–13 Indeed, GGT activity is a major determinant of redox state.3,12
To evaluate the impact of GGT activity on redox state as a function of the nature and the number of criteria of MS, we determined circulating levels of thiol compounds whose metabolism is under the control of GGT in a cohort of dyslipidemic patients in primary prevention.
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Methods |
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Patients
All patients were referred to our Prevention Center for Dyslipidemia and Cardiovascular Disease by their general practitioner and uniformly exhibited a history of dyslipidemia. All patients were in primary prevention and were requested to complete a questionnaire on their medical history, smoking habits, lifestyle and diet, and clinical status. Routine medical examination included weight, height (BMI was calculated as weight/(height)2), waist circumference, and repetitive blood pressure monitoring of the right arm for at least 30 minutes. Subjects with persistent systolic blood pressure
140 mm Hg or diastolic pressure 90 mm Hg or who were using antihypertensive drugs were considered as hypertensive. All patients underwent an electrocardiographic examination at rest. Patients included in the study displayed either hypercholesterolemia (serum LDL-cholesterol >160 mg/dL), or hypertriglyceridemia (serum triglycerides >150 mg/dL), or low serum HDL cholesterol levels (<35 mg/dL), or a combination of these features. Details of alcohol consumption were requested in a sample of patients (n=782) who were classified as heavy drinkers when estimated alcohol consumption was equal to or above 40 g per day.
Patients with hypothyroidism, malignant disease, severe renal insufficiency, cirrhosis, active liver disease attributable to viral infection (positive serology for virus hepatitis B and C), and those in secondary cardiovascular prevention were excluded. Patients with diabetes were also excluded.
Patients were classified as displaying metabolic syndrome on the basis of the modified Adult Treatment Panel III (ATPIII) criteria.13
Blood Samples and Analytical Methods
Blood samples were withdrawn by venipuncture between 8:00 and 9:30 AM after an overnight fast. Rigorous conditions for blood sampling and processing are essential for the accurate assessment of plasma thiol levels and were systematically standardized (see references8–14). Alanine amino transferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transpeptidase (GGT) activities were determined at 37°C according to Klauke et al.15 In a large group of healthy blood donors,16 upper normal values for men were established as 35, 32, and 42, for ALT, AST, and GGT, respectively, and for women as 26, 27, and 32, respectively.
Statistical Methodology
Results are expressed as mean (SD) and range for continuous variables and as number and percentage (%) for qualitative variables. We evaluated the relationships of each metabolic syndrome component relative to levels of glutathione, cysteinyl-glycine, and cysteine, and to GGT activity and compared patient groups on the basis of the number of metabolic syndrome criteria (respectively 0, 1, 2, 3, 4, and 5 criteria) which were concomitantly present. We performed ANOVA followed by post test for linear trend to determine whether the means of the column increased systematically with progressive increment in the number of metabolic syndrome components.17 To discriminate among the metabolic syndrome components and to determine whether their effect on GGT might be dominated by 1 or 2 specific MS components, we performed a multivariate logistic analysis with increase of GGT activity above normal range as the dependant dichotomic variable (0/1: normal/elevated). In addition, each of the 5 components in the multivariate analysis was entered in the analysis as a dichotomic variable (0/1: absent/present). Statistical analyses were carried out with the use of JMP (SAS Institute) software.
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Results |
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The major biological and clinical characteristics of the study population (n=1131) separated between patients with (n=295; 26%) or without metabolic syndrome are presented in Table 1. Twenty-one percent of overall patients were hypertensive and 43% were under treatment with lipid-lowering drugs. As expected, HDL-C levels were lower and triglyceride levels elevated in metabolic syndrome patients as compared with patients without this syndrome. However, plasma total cholesterol and LDL-cholesterol levels did not differ between the 2 groups including the subgroup of patients without lipid lowering treatment (LDL-C in untreated patients without metabolic syndrome=183±51 mg/dL, LDL-C in untreated patients with metabolic syndrome=175±54 mg/dL; P=0.11). By contrast, non–HDL-cholesterol levels were higher in metabolic syndrome patients as compared with subjects lacking the syndrome.
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The percentage of patients with ALT activities above the upper limit of normal values was 26% in the whole study population and was higher in patients with metabolic syndrome as compared with patients without metabolic syndrome (39% versus 21%, P<10–6).
Gamma GT activity was correlated with BMI (r=0.20; P<10–6) and waist circumference (r=0.27; P<10–6), but the partial correlation coefficient of BMI with GGT was no longer significant (r adj waist=–0.05; ns) although waist circumference remained significantly correlated with GGT (r adj BMI=0.19; P<10–6).
Among the thiol compounds, subjects presenting metabolic syndrome were distinguished by elevated plasma cysteinyl-glycine and cysteine levels and lower levels of GSH (P<10–6 for all comparisons as compared with those without the metabolic syndrome). Patients with metabolic syndrome were older than patients without; cysteinyl-glycine, glutathione, and GGT activity were not correlated with age (r=–0.01, –0.07, 0.02, respectively); only cysteine was significantly related to age (r=0.60; P<10–6). Creatinine levels were slightly higher (+3%) in the metabolic syndrome group (P=0.05). Adjustment of levels of glutathione, cysteinyl-glycine, and cysteine and GGT activity for age and creatinine did not modify mean values or statistical significance. Among the sample of patients in whom alcohol consumption was evaluated, 5.3% were heavy drinkers; the distribution of heavy drinkers between patients with and without metabolic syndrome was not distinct, but heavy drinkers displayed higher levels of GGT (44±39 UI versus 30±34 UI; P=0.01).
Transaminase activities were correlated with GGT (r=0.56 and r=0.51, respectively, for AST and ALT activity; P<10–6 for both) and glutathione (r=0.20 and r=0.25, respectively, for AST and ALT activity; P<10–6 for both), but the partial correlation coefficients for transaminases and glutathione were no longer significant when adjusted for GGT activity (r adj=0.03 and r adj=0.05, respectively, for AST and ALT activity).
We evaluated the potential relationships of each metabolic syndrome component relative to levels of glutathione, cysteinyl-glycine and cysteine, and to GGT activity (Table 2). Patients who exhibited at least 1 of the 5 components of the metabolic syndrome were distinguished by elevation in cysteinyl-glycine and cysteine levels, as well as GGT activity, but exhibited lower glutathione concentrations as compared with patients lacking any component of the metabolic syndrome. We next compared patient groups on the basis of the number of metabolic syndrome criteria which were concomitantly present (Table 3). As patients with 5 components of metabolic syndrome were rare (n=26), they were combined with patients displaying 4 criteria. Table 3A shows the progressive decrease in glutathione levels and the progressive increase in both cysteinyl–glycine and cysteine levels, and in GGT activity, as a function of the number of metabolic syndrome components in the overall population. The probability value for trend was highly significant for the progressive increment in the number of metabolic syndrome components for the 4 studied variables. As more than 40% of the patients were treated with lipid-lowering drugs, we performed the same analyses in the subgroup of patients not treated by lipid lowering drugs (n=646); the results were indistinguishable (Table 3B). Then, to determine whether the effect on GGT might be dominated by 1 or 2 of the MS constituents, we performed a logistic multivariate analysis in the group of patients without lipid lowering drug treatment with increase of GGT activity above the normal range as the dependant dichotomic variable (0/1: normal/elevated). Each of the 5 components of the metabolic syndrome was entered in the analysis as a dichotomic variable (0/1: absent/present); age (continuous) was also included in the multivariate analysis. Among the 5 components, 4 remained independently associated with increase in GGT (Table 4). Low HDL-cholesterol, a key criterion of metabolic syndrome, was not independently associated with increase in GGT, although there was a negative coefficient between HDL-C and GGT (r=–0.09; P=0.002), which became weaker and positive when adjusted on the basis of triglyceride levels (r adj=0.07; P=0.02). We subsequently performed the same analysis in the overall population and the results were similar.
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Lastly, as only dyslipidemic patients were involved in this study, 1 dichotomic variable corresponding to the presence or absence of pure hypercholesterolemia (type IIa), was included in the multivariate analysis; by definition, none of the patients with type IIa hypercholesterolemia displayed hypertriglyceridemia. We performed this analysis only in patients who were not under treatment with a lipid lowering drug. The findings did not differ however as the presence of triglyceride levels 150 mg/dL and elevated blood pressure 130/85 mm Hg, fasting blood glucose 5.5 mmol/L, and increase in waist circumference 102 cm for men and 88 cm for women, were all significantly associated with increase in GGT.
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Discussion |
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Our cross-sectional study of dyslipidemic patients displaying metabolic syndrome has revealed that significant elevation in GGT activity was closely associated with a potentially prooxidant profile of circulating thiol compounds, as demonstrated by low plasma levels of glutathione and by elevated concentrations of cysteine-glycine and cysteine. Such a profile is indicative of oxidative stress, an emerging CV risk factor.18 Furthermore, incremental modifications in these parameters occurred in parallel with increase in the number of components of the metabolic syndrome. Finally, multivariate analysis revealed that 4 of the 5 components of the metabolic syndrome were significantly associated with increase in GGT. The well-known strong inverse relationship of triglyceride and HDL-cholesterol levels19 is a plausible explanation for the absence of significant contribution of low HDL-cholesterol levels to the increase in GGT.
We and others have demonstrated that circulating GGT and transaminases activities are elevated in patients with metabolic syndrome.2,8,20 Moreover several epidemiological studies have demonstrated that GGT is a risk factor for CVD.1–2,20,21 Recently, Ruttmann et al1 showed that GGT activity was independently associated with cardiovascular mortality; indeed these findings in a large unselected cohort confirmed an association of progressive increase in GGT activity with overall mortality and cardiovascular events. Additionally, GGT was significantly correlated with several components of the metabolic syndrome, although waist circumference was not measured.22 We observed that BMI was no longer correlated with GGT when adjusted for waist circumference. The association of elevated GGT levels with MS is mediated by insulin resistance and central obesity, and is associated with hepatic steatosis.23,24 Several studies25–27 observed that elevated GGT activity is associated with the key features of MS, and that it is equally an independent predictor of diabetes, leading to the conclusion that this association may reflect both hepatic steatosis and enhanced oxidative stress.28 Furthermore, ALT activity was increased in patients with metabolic syndrome. Moreover, as we excluded patients with positive serology for virus hepatitis B and C and cirrhosis, elevated ALT may be indicative of steatohepatitis.29
In the context of oxidative stress,18,30,31 GGT may contribute to the pathogenesis of atherosclerosis,3 as its systemic activity is associated with generation of ROS.32 Furthermore GGT activity has been detected in atheromatous plaques in carotid and coronary arteries.33,34 Glutathione is the principal nonprotein thiol involved in antioxidant cellular defense, and plasma levels of GSH observed in this study are concordant with those in the literature.35,36 Glutathione levels were significantly decreased in our metabolic syndrome patients. In the study of Morrison et al,37 plasma glutathione levels were determined in adolescents; those with parents with known CHD exhibited lower concentrations than adolescents without a family history of CHD. Furthermore, adolescents with higher GGT activity displayed higher BMI, central adiposity and plasma triglyceride levels, and lower HDL-C concentrations, all of which correspond to key features of the metabolic syndrome. Recently Ashaq et al38 demonstrated a direct relationship between oxidative stress as estimated by determination of plasma levels of glutathione and cysteine and redox state, and early subclinical atherosclerosis as assessed by ultrasound evaluation of carotid intima-media thickness. In this context, it is relevant that glutathione-related antioxidant defenses are decreased in human atherosclerotic plaque tissue.39
Circulating levels of cysteinyl–glycine derived from the hydrolysis of GSH were significantly elevated in our patients with metabolic syndrome. Cysteinyl-glycine is a potent reducer of iron in the extracellular milieu and can generate Fe2–, thereby triggering iron-dependent production of reactive oxygen species (ROS),40 which may in turn initiate oxidation of low-density lipoprotein.41 Indeed, oxidized LDL particles exert potent proinflammatory activity because of their content of oxidized phospholipids,42 components which could partially account for the pathophysiological link between elevated GGT activity and atherogenesis.33
Levels of cysteine, equally a product of GSH cleavage, were also elevated. In this context, it is relevant that plasma levels of cysteine, a putative biomarker of cardiovascular risk, tend to be elevated in dyslipidemic patients with premature atherosclerosis and coronary heart disease.9 Indeed cysteine may function as an extracellular regulating factor for thiol disulfide exchange, and may in this way act to maintain adequate redox status.43 Furthermore, this readily oxidizable compound may give rise to the production of free radical species,44 thereby promoting oxidative damage of low-density lipoprotein.41
Our study prompts new hypotheses regarding the pathophysiological mechanisms which might underlie the role of GGT in promoting vascular disease in metabolic syndrome.45–52 Thus the graded increase in levels of cysteinyl-glycine and cysteine, and in GGT activity, as a function of progressive decrease in GSH concentrations, suggests a relationship between these factors. Indeed, linkage of glutamate to cysteine via the -carbon renders GSH refractory to standard proteases and only one enzyme is known to hydrolyze the -glutamyl bond in the extracellular milieu.3,4 This reaction produces cysteinyl-glycine. Thus metabolism of GSH initiated by GGT may lead to altered redox state and oxidative damage.3,4,12 These GGT-mediated reactions catalyze the oxidation of LDL,33,52 and elevated levels of oxidatively-modified LDL are associated with enhanced atherogenicity.54–56 In this context, it is highly relevant that we have previously demonstrated that metabolic syndrome in dyslipidemic patients is intimately associated with elevated systemic levels of 8-isoprostanes,53 an integrative marker of oxidative stress.18,46
As our study is based on a selected population, it exhibits significant limitations. Indeed, all participants were dyslipidemic; the majority of patients with metabolic syndrome in the general population do however display hypertriglyceridemia or low HDL-cholesterol levels.19,54–56 Thus, we included a large population sample and observed similar results to those observed in other investigations with respect to GGT activity and the levels of thiol compounds in metabolic syndrome. Our analysis was also limited by the cross-sectional design of the study and we were unable to infer causality. Nonetheless, this observational study can be considered as hypothesis generating. Lastly, in the absence of data on liver fat content, we cannot determine whether increase in GGT activity is directly associated with modification in thiol levels, or whether it reflects higher liver fat content.24 Indeed we cannot exclude the possibility that fatty liver might be directly related to modification of thiol metabolism.
Conclusion
We evaluated components of the redox system in dyslipidemic patients with metabolic syndrome as a function of the number of criteria. Our findings suggest that metabolic syndrome is characterized by elevated GGT activity which is associated with a cascade of abnormalities in the thiol redox system.
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Acknowledgments |
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Sources of Funding
This study was supported by Assistance-Publique–Hopitaux de Paris and INSERM. M.J.C. gratefully acknowledges the award of a "Contrat d’Interface APHP/INSERM".
Disclosures
None.
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Footnotes |
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Original received July 20, 2007; final version accepted December 27, 2007.
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