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© 2008 American Society for Nutrition J. Nutr. 138:903-907, May 2008

Nutrition and Disease

PPAR{gamma} mRNA Expression Is Reduced in Peripheral Blood Mononuclear Cells after Fat Overload in Patients with Metabolic Syndrome1,2

Manuel Macias-Gonzalez3–5*, Fernando Cardona3–5, Maribel Queipo-Ortuño5, Rosa Bernal4,5, Miguel Martin4,5 and Francisco J. Tinahones4,6

4 CIBER Fisiopatología de la Obesidad y Nutrición, CB06/03, Instituto de Salud Carlos III, Madrid 28029, Spain; 5 Fundación IMABIS, Laboratorio de Investigación, Málaga 29010, Spain; and 6 Servicio de Endocrinología, Hospital Virgen de la Victoria, Málaga 29010, Spain

* To whom correspondence should be addressed. E-mail: mmacias.manuel{at}gmail.com.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
PPAR{gamma} is a transcriptional regulator of metabolism; its activity can be modulated by direct binding of dietary lipids. The most prevalent human PPAR{gamma} gene variant, Ala12, is associated with postprandial hypertriglyceridemia in patients with metabolic syndrome, although the mechanism whereby this polymorphism affects lipid homeostasis remains to be fully determined. Using peripheral blood mononuclear cells (PBMC), we studied the effect of the Pro12 and Ala12 polymorphisms on mRNA expression of PPAR{gamma} and nuclear factor kappa B genes before and 3 and 4 h after fat overload. We also studied several biochemical and oxidative stress variables. Most of the indicators of oxidative stress were higher in patients with metabolic syndrome than in healthy subjects before and after fat overload. Patients also differed depending on whether they had the Pro12 or Ala12 variant in PBMC; PPAR{gamma} expression was lower in healthy subjects compared with patients. After fat overload, circulating triglycerides and PPAR{gamma} expression were positively correlated (r = 0.617, P < 0.05), and PPAR{gamma} expression tended to be negatively correlated with 2 important markers of oxidative stress: plasma lipid peroxidation (r = –0.224, P < 0.1) and carbonylated proteins (CPro) (r = –0.340, P < 0.1) concentrations. We also found differences in several indicators of oxidative stress between Pro12 and Ala12 patients, including an increase in plasma CPro before and after fat overload in Ala12 but not Pro12 patients. These data provide evidence that the Ala12 sequence variant is associated with a worse metabolic profile than Pro12. This is related to differences in the expression of PPAR{gamma} and to oxidative imbalance after fat overload.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
The increase in circulating triglycerides (TG)7 after fat intake is defined as postprandial hyperlipidemia, a component of metabolic syndrome (1). The "lipid sensing" PPAR{gamma} gene is a good candidate gene to study in patients with metabolic syndrome because it is a transcriptional regulator of metabolism, and its activity can be modulated by direct binding of dietary lipids. It enhances macrophage lipid uptake as well as lipid export (2). PPAR{gamma} is expressed by human peripheral blood mononuclear cells (PBMC), such as macrophages and monocytes (3–6), where it plays an important role in the regulation of the inflammatory processes (2). Furthermore, PPAR{gamma} downregulates proinflammatory mediators in macrophages (7). However, the pathophysiological importance of PPAR{gamma} in these extra adipose cells and tissues is not yet clear. Moreover, ligands of PPAR{gamma} inhibit the production of inflammatory cytokines, such as tumor necrosis factor-{alpha}, in monocytes (8). Several antiinflammatory mechanisms have been suggested, including inhibition of nuclear factor kappa B (NF-{kappa}B) by PPAR{gamma} (7).

The most prevalent human PPAR{gamma} gene variant is a polymorphism replacing alanine with proline at codon 12 (Ala12). Greater concentrations of TG and lower concentrations of HDL cholesterol occur in obese persons with familial combined hyperlipidemia who carry the Ala12 allele (9). Similar alterations in the blood lipid profile are seen in heterozygous lipoprotein lipase (LPL) deficiency in obese individuals (10). In vitro studies have shown that the Ala12 variant is less effective at activating target genes, such as the LPL gene (11). The LPL enzyme hydrolyzes TG in circulating chylomicrons and VLDL, releasing fatty acids, chylomicron remnants, and LDL cholesterol. Discrepancies in epidemiological studies may arise from the presence of linked sequence variants of functional significance in the PPAR{gamma} gene, some of which may oppose the effect of Ala12 (12). We have recently demonstrated the association between the Ala12 sequence variant of the PPAR{gamma} gene in patients with diabetes and metabolic syndrome (13,14). However, the mechanism whereby this polymorphism affects lipid homeostasis remains to be fully determined.

Clinical studies have shown that increased postprandial concentrations of TG are associated with arteriosclerosis (15) and insulin resistance (16). Studies in healthy volunteers have shown that postprandial hyperlipidemia causes a marked increase in oxidative stress and a worsening in endothelial function (17). Many researchers consider oxidative stress to play an important role in the pathogenesis of cardiovascular disease (18), diabetes (19), and metabolic syndrome (20). The postprandial TG enrichment of VLDL may lead to increased production of lipid-derived free radicals and reactive oxygen species. When the generation of reactive oxygen species exceeds the availability of antioxidant defense mechanisms, oxidative stress ensues (21).

Our group recently found that fat overload induces oxidative damage in healthy subjects and in patients with metabolic syndrome (22), and the Ala12 sequence variant is associated with a high risk for postprandial lipidemia in patients with metabolic syndrome (14). We therefore analyzed the mRNA expression of PPAR{gamma} and NF-{kappa}B in PBMC from healthy control subjects and patients with metabolic syndrome before and after fat overload. Additionally, we studied the association between the Ala12 polymorphism and biochemical and oxidative stress parameters before and after fat overload.


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Patients. Participants fasted overnight and then blood samples were taken from the 8 healthy persons with no criteria for metabolic syndrome and 16 patients with metabolic syndrome. No subject had experienced any weight change over the previous 3 mo, and an oral glucose tolerance test was performed in all participants to exclude any carbohydrate metabolism disorder. All the participants consumed a 60-g fat overload with a liquid commercial preparation (Supracal; SHS International). Only water was permitted during the process and no physical exercise was undertaken. The commercial preparation of 0.125 L contained 60 g fat, of which 12 g were saturated, 35.35 g were monounsaturated fatty acids, and 12.75 g were polyunsaturated fatty acids. Each 0.1 L contained <1 g lauric acid, 1 g myristic acid, 4.8 g palmitic acid, 1.4 g stearic acid, 27.7 g oleic acid, 9.6 g linoleic acid, 1.4 g behenic acid, and 0.5 g lignoceric acid. The preparation contained no proteins or carbohydrates. All subjects gave informed consent to the study, which was approved by the Ethics Committee of the Virgen de la Victoria University Hospital.

    Isolation of PBMC and DNA analysis. Samples of venous blood were obtained before (baseline) and 3 and 4 h after fat overload. Plasma and serum were separated by centrifugation (1000 x g; 5 min), and the PBMC were isolated from anticoagulant-treated blood by Ficoll standard density gradient centrifugation (1000 x g; 5 min) (6). DNA was isolated and the Ala12 sequence variant was analyzed by restriction fragment length polymorphism enzyme digestion (14).

    Variables measured. We recorded the age (in years) of all subjects and measured their weight, height (to calculate the BMI, calculated as the weight in kg divided by the height in m squared), and waist circumference. Serum samples were used to assess the values of insulin resistance and insulin secretion, calculated, respectively, as follows: homeostasis model assessment of insulin resistance (HOMA-IR) = [fasting insulin (pmol/L) x fasting glucose (mmol/L)/22.5] (23) and homeostasis model assessment of B-cell activity (HOMA-B) = [20 x fasting insulin (pmol/L)/fasting glucose (mmol/L) – 3.5 HOMA-B] (24). Serum glucose, total protein, uric acid, cholesterol, TG, and HDL cholesterol concentrations were measured in a Dimension autoanalyzer (Dade Behring). Serum insulin concentration was quantified by RIA (BioSource). Plasma samples were used to determine all indicators of oxidative stress: lipid peroxidation (LPO) products (malondialdehyde + 4-hydroxyalkenals), total glutathione [oxidized (GSSG) and reduced glutathione (GSH)], GSH levels and GSH reductase activity, using reagents purchased from Oxis International (i.e., LPO-586, GSH-420, and GR-340 kits, respectively). Additionally, glutathione sulfur transferase activity was evaluated using the GST Colorimetric Activity kit (BioVision). The GSSG concentration was calculated using the following equation: GSSG = total glutathione – GSH. Plasma carbonylated protein (CPro) was evaluated using the method of Levine et al. (25). Plasma GSH peroxidase and catalase (CAT) activity were assayed following the Flohé and Gunzler (26) method and the Aebi (27) technique.

    Real-time quantitative PCR. Total RNA from PBMC was prepared using Trizol reagent (Gibco BRL Life Technologies) according to the manufacturer's instructions. cDNA was obtained from 1 µg of total RNA (28). The cDNA obtained was used as a template for real-time quantitative PCR. The primers for the PCR (Sigma-Proligo) were as follows: 5' CGACCAAGTAACTCTCCTCA-3' (PPAR{gamma} forward) and 5'-GTTCGTGACAATCTGTCTG-3' (PPAR{gamma} reverse) and 5'-AGTCCTGCTCCTTCCAAAAC-3' (NF-{kappa}B forward) and 5'-CTTCGGTGTAGCCCATTTGT-3' (NF-{kappa}B reverse). Reaction mixtures contained 4 µL of LightCycler FastStartPLUS DNA mastermix for SYBR Green I (Roche Diagnostic), 0.5 µmol/L of each primer, 4 mmol/L MgCl2, and 2 µL of template DNA in a final reaction volume of 20 µL (29). A standard curve was created with serial dilutions of a PCR fragment from human adipose tissue total RNA (Clontech Laboratories). The levels of mRNA were normalized to the amount of human β-actin, a constitutively expressed gene. The following are the primer pairs used for β-actin: forward 5'-AACTGGAACGGTGAAGGTGAC-3' and reverse 5'-TGTGGACTTGGGAGAGGACTG (29).

    Statistical Analysis. Data are expressed as means ± SD. Comparisons between baseline and post fat overload were made using the Wilcoxon test for paired-sample. The comparison between the 2 polymorphism groups or between healthy persons and patients of the 2 polymorphism groups combined were analyzed using the independent-sample, nonparametric Mann-Whitney test. The Pearson correlation coefficients among study variables were calculated. Values were considered to be significant when P < 0.05 for 2-tailed analyses. The analyses were performed with SPSS, version 11.5.


   Results
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
In the group of 16 patients with metabolic syndrome, the 2 sequence variants (8 Pro12 and 8 Ala12) did not differ in baseline characteristics (Table 1). However, carriers of the Ala12 allele had substantially lower insulin secretion (as measured by HOMA-B activity) compared with the Pro12 patients, whereas both groups of patients had higher insulin resistance than controls, as measured by HOMA-IR. Moreover, the carriers of the Pro12 allele were characterized by substantially greater BMI and higher fasting serum insulin concentration than controls. In general, the serum TG concentration was significantly lower in the healthy controls than in patients with metabolic syndrome, and the plasma indicators of oxidative stress were higher in patients with metabolic syndrome than in healthy controls before and after fat overload, such as plasma CPro and GSSG concentrations (Table 2). Moreover, plasma CPro and GSH concentrations were substantially higher before and after fat overload in patients with the Ala12 variant than in those with the Pro12 allele. In contrast, CAT activity was substantially lower before and after fat overload in patients with the Ala12 allele than in those with the Pro12 allele. Plasma LPO concentration was substantially higher in patients with metabolic syndrome than in healthy subjects, before and after fat overload. However, plasma LPO concentration increased substantially only in healthy subjects after fat overload (Table 2).


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  		TABLE 1 Baseline biological characteristics of the healthy persons and patients with the Pro12 or Ala12 polymorphism of the PPAR{gamma} gene1

 

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  		TABLE 2 Concentrations of different indicators of oxidative stress and circulating serum TG in healthy controls and metabolic syndrome patients with the Pro12 and Ala12 polymorphism before and 3 and 4 h after fat overload1

 
The mRNA expression level of PPAR{gamma} at baseline was substantially lower in healthy subjects than in patients with metabolic syndrome (Table 3). Additionally, after 3 h fat overload, PPAR{gamma} mRNA expression profile was similar for both sequence variants, although at baseline, carriers of the Ala12 allele showed a lower expression of the PPAR{gamma} gene than carriers of the Pro12 allele (Table 3). However, at 4 h the level tended (P < 0.1) to return to baseline values in Ala12, suggesting that the maximum peak was reached 3 h after fat overload (data not shown). The pattern of NF-{kappa}B mRNA expression did not change in all subjects after fat overload (Table 3).


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  		TABLE 3 Results of the PPAR{gamma} and NF-{kappa}B mRNA expression in PBMC by real-time quantitative PCR in healthy controls and metabolic syndrome patients with the Pro12 and Ala12 polymorphism before and 3 and 4 h after fat overload1

 
In healthy controls, serum TG concentrations were correlated with plasma GSSG concentration (r = 0.599, P < 0.05) and with PPAR{gamma} expression (r = 0.617, P < 0.05) after fat overload. In patients with metabolic syndrome, the expression of PPAR{gamma} was correlated with serum TG concentration (r = 0.617, P < 0.05) and with plasma GSSG concentration (r = 0.645, P < 0.05) after fat overload. Additionally, PPAR{gamma} expression tended to be negatively correlated with 2 indicators of oxidative stress: plasma LPO (r = –0.224, P < 0.1) and CPro (r = –0.340, P < 0.1) concentrations.


   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
We found that the expression of the PPAR{gamma} Ala12 polymorphism was associated with oxidative imbalance after a fat overload in patients with metabolic syndrome. It has been suggested that a "high cytokine responder" genotype associated with the acute phase response (APR) is found in patients with metabolic syndrome and that the effect of this APR is a "hypermetabolic state" (30). The APR and hypermetabolic state are associated with alterations in oxidative metabolism, increased production of free radicals, and oxidative stress (30–32). The APR has now been shown to downregulate PPAR{gamma} in adipose tissue, which is to be expected because PPAR{gamma} is generally antiinflammatory and improves insulin sensitivity (33). Taking these data together, it is reasonable to hypothesize that the expression of PPAR{gamma} is affected by the oxidative imbalance associated with postprandial hypertriglyceridemia and the "hypermetabolic state" found in patients with metabolic syndrome.

The healthy subjects experienced an increased expression level of PPAR{gamma} after fat overload compared with the baseline level, whereas the patients with metabolic syndrome showed a dramatic decrease, even though the baseline expression level was lower in carriers of the Ala12 than in Pro12 patients (Table 3).

The reason why the PPAR{gamma} response differed may be its positive correlation with the serum TG concentration, which leads to the concept of "saturation", derived from a limitation in fat expandability and peripheral lipid metabolism in pathophysiological situations (34). This saturation in lipid balance generates lipotoxicity, which may directly affect the regulation of PPAR{gamma} expression through the oxidative stress that is generated. In support of this model, our data showed a variation between healthy subjects and metabolic syndrome patients after fat overload in the correlations among PPAR{gamma}, oxidative stress markers, and TG concentration. Whereas both groups showed a significantly positive correlation between circulating TG and PPAR{gamma} expression, only the healthy subjects had a positive correlation between plasma GSSG and serum TG. The normal metabolic answer to an increase in the level of serum TG is accompanied by an increase in the expression of PPAR{gamma} to ensure the storage and relocalization of the excess TG. Obviously, such a strong increase in circulating levels of TG, even if it is counteracted by an increase in PPAR{gamma} expression, generates oxidative stress, which can be neutralized in healthy subjects via the antioxidant systems in the cells, with GSH conversion to GSSG being a major indicator of such action. This biochemical scenario is demonstrated by the positive correlation between serum TG and plasma GSSG levels in healthy controls. In contrast, this pivotal TG/GSSG correlation was lost after fat overload in the metabolic syndrome patients. Even if PPAR{gamma} remains correlated with the level of serum TG, the dramatic increase in circulating TG overwhelmed the capacity of PPAR{gamma} to relocate them. Hence, the oxidative imbalance generated by the lipotoxicity may also end in saturation of the antioxidant machinery, which could finally affect the expression of PPAR{gamma}. We also found a significant negative trend between PPAR{gamma} expression and 2 key markers for oxidative stress in plasma, LPO and CPro concentrations. This lack of significance may have been due to the number of subjects in each group.

Further, we found oxidative imbalance in patients with metabolic syndrome as compared with healthy subjects at baseline, which was accentuated after fat overload (Table 2). This interpretation is in accordance with very recent data supporting the model of lipotoxicity as a consequence of a failure in the metabolism and expandability of fat associated with PPAR{gamma} expression (34).

The metabolic syndrome patients had an elevated HOMA-IR, but more importantly, there was a striking difference between Pro12 and Ala12 patients in HOMA-B activity. The increase in insulin secretion capacity (more marked in the Pro12 patients, as measured with the HOMA-B) is considered to be a response mechanism to insulin resistance (30). Hence, the failure to achieve such a response by the Ala12 patients may show, to our knowledge for the first time, a direct association between the PPAR{gamma} gene sequence variant and a more pronounced defect in fat storage and relocation due to the imbalance between insulin resistance and secretion response. However, our data regarding the negative regulation of PPAR{gamma} expression and hypertriglyceridemia in the Ala12 patients suggest that another factor may be inducing this pathological condition in the cells, i.e., oxidative stress (20).

In confirmation of our hypothesis, we found some differences in several indicators of oxidative stress between Pro12 and Ala12 patients, such as a greater plasma CPro concentration and a lower CAT activity after fat overload in Ala12 subjects. This increase in CPro is an indicator of oxidation and it is already associated with diabetes and metabolic syndrome in relation to active glycolated elements. The damage induced by excess CPro and the signaling derived by the active glycolated elements pathway account for, among other dysfunctions, the HOMA-IR and HOMA-B in these patients (35,36).

The expression of PPAR{gamma} and postprandial hypertriglyceridemia due to oxidative stress leads to the question of what target genes of the inflammatory process are then affected by this negative regulation of the PPAR{gamma} gene. Therefore, we evaluated the possible connection between PPAR{gamma} and NF-{kappa}B expression because this transcription factor promotes oxidative stress (30). Surprisingly, our data showed that there was no correlation between the expression of these genes in all subjects before or after fat overload, with the expression level of NF-{kappa}B remaining constant (Table 3). Initially, these data may appear contradictory, but a molecular explanation may be considered. Even if the absolute value of NF-{kappa}B remains constant, the fraction of translocated and active forms of the protein may be altered by the change in PPAR{gamma}. However, the assay method used may be unable to measure the functionality of NF-{kappa}B.

In conclusion, our data show that postprandial hypertriglyceridemia was unambiguously associated with a fall in PPAR{gamma} expression in all metabolic syndrome patients. Additionally, oxidative stress appeared to play a key role after the increase in circulating TG, being the driver of PPAR{gamma} downregulation. Finally, this work presents a pathological association in patients with the Ala12 PPAR{gamma} gene sequence variant among postprandial hypertriglyceridemia, oxidative imbalance, and PPAR{gamma} expression.


   ACKNOWLEDGMENTS
 
We thank Mora Murri for excellent laboratory assistance and Ian Johnstone for help with the final English-language version.


   FOOTNOTES
 
1 Supported by research grants from the Instituto de Salud Carlos III (FIS PI04/0834 and CP04/0039) and the Ministerio de Ciencia y Tecnologia (SAF 2006/12894). Back

2 Author disclosures: M. Macias-Gonzalez, F. Cardona, M. Queipo-Ortuño, R. Bernal, M. Martin, and F. J. Tinahones, no conflicts of interest. Back

3 These authors contributed equally to this study. Back

7 Abbreviations used: APR, acute phase response; CAT, catalase; CPro, carbonylated proteins; GSH, reduced glutathione; GSSG, oxidized glutathione; HOMA-B, homeostasis model assessment of B-cell activity; HOMA-IR, homeostasis model assessment of insulin resistance; LPL, lipoprotein lipase; LPO, lipid peroxidation; NF-{kappa}B, nuclear factor kappa B; PBMC, peripheral blood mononuclear cell; TG, triglycerides. Back

Manuscript received 29 October 2007. Initial review completed 12 November 2007. Revision accepted 31 January 2008.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Balkau B, Charles MA, Drivsholm T, Borch-Johnsen K, Wareham N, Yudkin JS, Morris R, Zavaroni I, van Dam R, et al.; European Group For The Study Of Insulin Resistance (EGIR). Frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of an insulin resistance syndrome. Diabetes Metab. 2002;28:364–72.[Medline]

2. Lehrke M, Lazar MA. The many faces of PPAR{gamma}. Cell. 2005;123:993–9.[Medline]

3. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.[Medline]

4. Aicher A, Hayden-Ledbetter M, Brady WA, Pezzutto A, Richter G, Magaletti D, Buckwalter S, Ledbetter JA, Clar EA. Characterization of human inducible costimulator ligand expression and function. J Immunol. 2000;164:4689–96.[Abstract/Free Full Text]

5. Setoguchi K, Misaki Y, Terauchi Y, Yamauchi T, Kawahata K, Kadowaki T, Yamamoto K. Peroxisome proliferator-activated receptor-gamma haploinsufficiency enhances B-cell proliferative responses and exacerbates experimentally induced arthritis. J Clin Invest. 2001;108:1667–75.[Medline]

6. Klotz L, Schmidt M, Giese T, Sastre M, Knolle P, Klockgether T, Heneka TM. Proinflammatory stimulation and pioglitazone treatment regulate PPAR{gamma} levels in PBMCs from healthy controls and multiple sclerosis patients. J Immunol. 2005;175:4948–55.[Abstract/Free Full Text]

7. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-{kappa}B signaling pathway. Proc Natl Acad Sci USA. 2000;97:4844–9.[Abstract/Free Full Text]

8. Sharma AM, Staels B. Peroxisome proliferator-activated receptor gamma and adipose tissue-understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab. 2007;92:386–95.[Abstract/Free Full Text]

9. Vaccaro O, Mancini FP, Ruffa G, Sabatino L, Iovine C, Masulli M, Colantuoni V, Riccardi G. Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene in healthy individuals. Clin Endocrinol (Oxf). 2002;57:481–6.[Medline]

10. Julien P, Vohl MC, Gaudet D, Gagné C, Lévesque G, Després JP, Cadelis F, Brun LD, Nadeau A, Ven Murthy MR. Hyperinsulinemia and abdominal obesity affect the expression of hypertriglyceridemia in heterozygous familial lipoprotein lipase deficiency. Diabetes. 1997;46:2063–8.[Abstract]

11. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J. PPAR{alpha} and PPAR{gamma} activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996;15:5336–48.[Medline]

12. Meirhaeghe A, Amouyel P. Impact of genetic variation of PPAR{gamma} in humans. Mol Genet Metab. 2004;83:93–102.[Medline]

13. Soriguer F, Morcillo S, Cardona F, Rojo-Martinez G, Almaraz MC, Ruiz de Adana MS, Olveira G, Tinahones F, Esteva I. Pro12Ala polymorphism of the PPAR{gamma}2 is associated with type 2 diabetes mellitus and peripheral insulin sensitivity in a population with a high intake of oleic acid. J Nutr. 2006;136:2325–30.[Abstract/Free Full Text]

14. Cardona F, Morcilo S, Gonzalo-Marin M, Garrido-Sanchez L, Macias-Gonzalez M, Tinahones FJ. Pro12Ala sequence variant of the PPAR{gamma} gene is associated with postprandial hypertriglyceridemia in non-E3/E3 patients with the metabolic syndrome. Clin Chem. 2006;52:1920–5.[Abstract/Free Full Text]

15. Karpe F. Postprandial lipoprotein metabolism and atherosclerosis. J Intern Med. 1999;246:341–55.[Medline]

16. Ceriello A. The postprandial state and cardiovascular disease: relevance to diabetes mellitus. Diabetes Metab Res Rev. 2000;16:125–32.[Medline]

17. Tushuizen ME, Nieuwland R, Scheffer PG, Sturk A, Heine RJ, Diamant M. Two consecutive high-fat meals affect endothelial-dependent vasodilation, oxidative stress and cellular microparticles in healthy men. J Thromb Haemost. 2006;4:1003–10.[Medline]

18. Tushuizen ME, Diamant M, Heine RJ. Postprandial dysmetabolism and cardiovascular disease in type 2 diabetes. Postgrad Med J. 2005;81:1–6.[Abstract/Free Full Text]

19. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991;40:405–12.[Abstract]

20. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–61.[Medline]

21. Saxena R, Madhu SV, Shukla R, Prabhu KM, Gambhir JK. Postprandial hypertriglyceridemia and oxidative stress in patients of type 2 diabetes mellitus with macrovascular complications. Clin Chim Acta. 2005;359:101–8.[Medline]

22. Cardona F, Tunez I, Tasset I, Garrido-Sanchez L, Collantes E, Tinahones FJ. Circulating antioxidant defences are decreased in healthy people after a high fat meal. Br J Nutr. 2008;99:44–8.[Medline]

23. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110:1564–71.[Abstract/Free Full Text]

24. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–95.[Abstract/Free Full Text]

25. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464–78.[Medline]

26. Flohé L, Gunzler WA. Assays of glutathione peroxidase. Methods Enzymol. 1984;105:114–21.[Medline]

27. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121–6.[Medline]

28. Serrano A, del Arco I, Pavon FJ, Macias M, Perez-Valero V, Rodriguez de Fonseca F. The cannabinoid CB1 receptor antagonist SR141716A (Rimonabant) enhances the metabolic benefits of long-term treatment with oleoylethanolamide in Zucker rats. Neuropharmacology. 2008;54:226–34.[Medline]

29. Queipo-Ortuño M, de Dios Colmenero J, Macias M, Bravo MJ, Morata P. Preparation of bacterial DNA template by boiling and effect of immunoglobulin G as an inhibitor in real-time PCR for serum samples from patients with brucellosis. Clin Vaccine Immun. 2008;15:293–6.

30. Nunn AV, Bell J, Barter P. The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. Nucl Recept. 2007;25:1.

31. Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol. 2007;47:142–56.[Medline]

32. Rosenson RS, Wolff DA, Huskin AL, Helenowski JB, Rademaker AW. Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects with hypertriglyceridemia and the metabolic syndrome. Diabetes Care. 2007;30:1945–51.[Abstract/Free Full Text]

33. Lu B, Moser AH, Shigenaga JK, Feingold KR, Grunfeld C. Repression of type II nuclear hormone receptors, receptor CoA and their target genes in adipose tissues during the acute-phase response. J Lipid Res. 2006;47:2179–90.[Abstract/Free Full Text]

34. Medina-Gomez G, Gray SL, Yetukuri L, Shimomura K, Virtue S, Campbell M, Curtis RK, Jimenez-Linan M, Blount M, et al. PPAR{gamma}2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet. 2007;3:634–47.

35. Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A. Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med. 2006;10:389–406.[Medline]

36. Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A. Protein carbonylation in human diseases. Trends Mol Med. 2003;9:169–76.[Medline]





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