HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fontaine-Bisson, B. Articles by El-Sohemy, A. Search for Related Content PubMed PubMed Citation Articles by Fontaine-Bisson, B. Articles by El-Sohemy, A. Agricola Articles by Fontaine-Bisson, B. Articles by El-Sohemy, A.

Genetic polymorphisms of tumor necrosis factor- modify the association between dietary polyunsaturated fatty acids and fasting HDL-cholesterol and apo A-I concentrations^1,2,3

¹ From the Department of Nutritional Sciences (BF-B, TMSW, RGJ, LAL, and AE-S), the Departments of Laboratory Medicine and Pathobiology and Medicine (PWC), and the Department of Public Health Sciences (PNC), University of Toronto, Toronto, Canada; the Departments of Medicine (JLC) and Nutrition (RRL), Université de Montréal and Research Center, Centre Hospitalier de l'Université de Montréal, Montreal, Canada; the Department of Medicine, Division of Endocrinology and Metabolism, Université de Sherbrooke, Sherbrooke, Canada (PM); St Michael's Hospital, Toronto, Toronto, Canada (TMSW, RGJ, and LAL); St Joseph's Health Centre, London, Canada (NWR); the Heritage Medical Research Centre, Edmonton, Canada (EAR); and the Department of Medicine, St Michael's Hospital, Toronto, Toronto, Canada (PWC)

² Supported by a grant from the Canada Institutes of Health Research (CIHR- MCT-44205) and the Advanced Foods and Materials Network. BF-B is a recipient of a Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship. AE-S holds a Canada Research Chair in Nutrigenomics.

³ Reprints not available. Address correspondence to A El-Sohemy, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, FitzGerald Building, Room 350, 150 College Street, Toronto, ON, M5S 3E2, Canada. E-mail: a.el.sohemy{at}utoronto.ca.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background:Heterogeneity in circulating lipid concentrations in response to dietary polyunsaturated fatty acids (PUFAs) may be due, in part, to genetic variations. Tumor necrosis factor- (TNF-) is a proinflammatory cytokine that can induce hyperlipidemia and is known to be modulated by dietary PUFAs.

Objective:The objective was to determine whether TNF- genotypes modify the association between dietary PUFA intake and serum lipid concentrations.

Design:The study involved 53 men and 56 women aged 42–75 y with type 2 diabetes. Dietary intakes were assessed with the use of a 3-d food record, and blood samples were collected to determine fasting serum lipids. DNA was isolated from blood for genotyping by polymerase chain reaction–restriction fragment length polymorphism for the TNF- –238GA and –308GA polymorphisms.

Results:PUFA intake was positively associated with serum HDL cholesterol in carriers of the –238A allele (ß = 0.06 ± 0.03 mmol/L per 1% of energy from PUFAs; P = 0.03), but negatively associated in those with the –238GG genotype (ß = –0.03 ± 0.01, P = 0.03) (P = 0.004 for interaction). PUFA intake was inversely associated with HDL cholesterol in carriers of the –308A allele (ß = –0.07 ± 0.02, P = 0.002), but not in those with the –308GG genotype (ß = 0.02 ± 0.02, P = 0.13) (P = 0.001 for interaction). A stronger gene x diet interaction was observed when the polymorphisms at the 2 positions (–238/–308) were combined (P = 0.0003). Similar effects were observed for apolipoprotein A-I, but not with other dietary fatty acids and serum lipids.

Conclusion:TNF- genotypes modify the relation between dietary PUFA intake and HDL-cholesterol concentrations. These findings suggest that genetic variations affecting inflammation may explain some of the inconsistencies between previous studies relating PUFA intake and circulating HDL.

Key Words: Tumor necrosis factor- • genotype • polyunsaturated fatty acids • HDL cholesterol • apolipoprotein A-I • type 2 diabetes

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Polyunsaturated fatty acids (PUFAs) have been shown to have some protective cardiovascular effects by influencing many risk factors including serum lipids (1). The n–3 PUFAs that are derived mainly from fish oils (EPA and DHA) are known to lower plasma triacylglycerols, whereas n–6 PUFAs have been shown to reduce total and LDL cholesterol (1). The effects of these 2 classes of PUFAs on other lipids and lipoproteins are not consistent, and the reasons for these inconsistencies are unclear. Chronic inflammation has been associated with dyslipidemia (2) and may mediate the effects of PUFAs on lipid metabolism (3).

PUFAs are precursors of prostaglandins and leukotrienes and also affect the expression of various genes involved in inflammation (3). Tumor necrosis factor- (TNF-) is a major proinflammatory cytokine that has been associated with an altered lipid profile, insulin resistance, and an increased risk of cardiovascular disease (CVD) (4, 5). Different types of fatty acids, such as n–3 and n–6 PUFAs, modulate the production of TNF- in humans (6–9). A genetic polymorphism of TNF- has also been shown to influence the effect of dietary n–3 PUFAs on TNF- production in humans (6). TNF- alters lipid metabolism by inducing lipolysis in adipose tissue (10), increasing lipogenesis in the liver (11), and worsening the serum lipid profile (12, 13). TNF- has also been shown to alter the expression of genes involved in lipid metabolism, such as lipoprotein lipase (LPL) (14); proliferator activated receptors (PPARs) (15); apolipoprotein (apo) A-I, apo A-IV, and apo E (16, 17); and lecithin:cholesterol acyltransferase (18).

Two common genetic polymorphisms in the promoter region of the TNF- gene have been shown to alter transcriptional activity (19–21). A single nucleotide polymorphism (SNP) at position –238GA has been shown to decrease the rate of transcription and production of the cytokine (19), whereas an SNP at position –308GA has been shown to increase both (20, 21). TNF- inhibits insulin action, and chronic inflammation is typically found in type 2 diabetes (22). We therefore investigated whether TNF- genotypes modify the association between dietary PUFA intake and serum lipid concentrations among individuals with type 2 diabetes.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Subjects were participants in the Canadian trial of dietary Carbohydrate in Diabetes study. Of the 164 participants recruited, blood samples for genotyping, complete dietary information, and lipid profiles were available for 109 subjects. The study participants were recruited over a 1-y period (2002–2003) in 5 cities across Canada (Edmonton, London, Montreal, Sherbrooke, and Toronto). Subjects were men (n = 53) and women (n = 56) with type 2 diabetes treated by diet alone and with a body mass index (BMI; in kg/m²) of 25. The diagnosis of diabetes was made according to the Canadian Diabetes Association criteria; subjects had to have either a fasting plasma glucose concentration 7.0 mmol/L or a plasma glucose concentration 11.1 mmol/L 2 h after a 75-g oral-glucose-tolerance test within 2 mo before the start of the study. The glycated hemoglobin (Hb A_1c) value had to be 130% of the upper limit of normal of the local hospital's laboratory. Subjects taking lipid-lowering drugs [statins (n = 46), fibrate (n = 2), or both (n = 5) or unavailable information (n = 8)] were not excluded from the study to make the results more applicable to the diabetic population. Subjects were excluded if they were taking antidiabetic medications; had a major cardiovascular event or surgery within the previous 6 mo before enrollment in the study; had a serum triacylglycerol concentration >10 mmol/L; had a major debilitating disorder such as liver disease, renal failure, cancer, or gastrointestinal disorder; or used medication that was likely to alter gastrointestinal motility, nutrient absorption, or insulin sensitivity. The study protocol was approved by the ethics review committee at each participating institution, and informed consent was obtained from all subjects.

Blood measurements
Fasting serum cholesterol and triacylglycerol were measured by using the Technicon RA100 (Technicon, Miami, FL). HDL cholesterol was measured in the supernatant fluid after treatment of serum with dextran sulfate magnesium chloride. Serum free fatty acids (FFAs) were measured by enzymatic activation by long-chain fatty acid-CoA ligase (Wako Chemical Industries, Dallas, TX). Apo A-I and apo B were measured by nephelometry, and serum high-sensitivity C-reactive protein (hs-CRP) was determined by using the Behring BN100 hs-CRP reagent (Dade-Behring, Mississauga, Canada). All of the above were measured at the J Alick Little Lipid Research Laboratory of St Michael's Hospital (Toronto, Canada). Plasma insulin was measured by electrochemiluminescence immunoassay and plasma glucose by hexokinase glucose HK liquid at the University of Toronto's Banting and Best Diabetes Centre Core Laboratory. LDL cholesterol was calculated by using the Friedewald equation for samples with triacylglycerol values <4.52 mmol/L (23).

Genotyping
DNA was isolated from peripheral white blood cells by using the GenomicPrep Blood DNA Isolation kit (Amersham Pharmacia Biotech Inc, Piscataway, NJ). Genotyping of the –238GA (rs361525) and –308GA (rs1800629) polymorphisms was performed by polymerase chain reaction–restriction fragment length polymorphism analysis as previously described (24).

Dietary and physical activity assessment
Dietary intake was assessed the week before the blood sample collection with the use of a 3-d food record. Subjects recorded their food and beverage consumption during 2 weekdays and 1 weekend day. The nutrient composition of the diet was assessed by using an in-house program with a nutrient database that was based on the Canadian Nutrient File (25). Physical activity was assessed by using the Modifiable Activity Questionnaire from which an MET (metabolic equivalent) score was calculated (26).

Statistical analysis
One-factor analysis of variance was used to test for differences in general characteristics between the 3 genotypes of the TNF- polymorphisms. The non-normally distributed variables (glucose, insulin, triacylglycerol, and C-reactive protein) were log_e transformed, and the results are presented as the antilog of the estimate. Although the distribution for apo A-I was slightly skewed, no transformation was performed to generate results that can be readily interpreted. Nevertheless, this approach gave similar results to the transformed data, but yielded a more conservative estimate. The chi-square test was used to analyze categorical variables. The 2 polymorphisms were not in linkage disequilibrium (r² = 0.009 calculated by using the HAPLOVIEW software package) (27). Because of the sample size, homozygotes for the minor allele (AA) were grouped with heterozygotes (GA) for each of the 2 polymorphisms (–238GA and –308GA) producing 4 possible combinations for –238/-308: 0/0, 0/1, 1/0, and 1/1, where 0 = GG and 1 = AA+GA. The fourth combined genotype with the 2 minor alleles was dropped from the analyses because of the small sample size (n = 7). Multiple linear regression was used to test whether the effect of different dietary fatty acids on serum lipid and apolipoprotein concentrations varied across the different genotypes (interaction) in the presence of various confounders. Of the variables age, energy intake, alcohol consumption, lipid-lowering drugs, Hb A_1c, physical activity, BMI, and sex, only the latter 2 variables were statistically significant and thus remained in the final model. No differences or interactions were found between the TNF- genotypes and any of these potential confounders. Dietary fatty acids were adjusted for total energy intake by using both the residual and the nutrient density methods (28). Although similar results were obtained with both methods, values from the nutrient density method (% of energy of dietary fatty acids from total energy intake), which yielded more conservative estimates, are reported. Similar results were obtained when interactions were tested with PUFAs as a continuous variable and when grouped into tertiles. Men and women were analyzed together because patterns were similar between them, and no interactions between sex and TNF- genotypes on the outcome measures of interest were found. Departure of genotype distributions from Hardy-Weinberg equilibrium was assessed by using the chi-square test with 1 df and confirmed by using the HAPLOVIEW software package (27). Significant P values are 2-sided and <0.05. The Bonferroni correction for multiple comparisons was used when appropriate. All statistical analyses were performed by using SAS version 9.1 (SAS Institute Inc, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Anthropometric, biochemical, and dietary characteristics of the subjects are summarized in Table 1. The minor allele frequencies were 14.2% for the –238GA polymorphism and 20.6% for the –308GA polymorphism. The distributions of the 3 genotypes for each of the 2 SNPs (–238GG = 82, GA = 23, AA = 4; and –308GG = 69, GA = 35, AA = 5) were in Hardy-Weinberg equilibrium. No differences were observed between genotypes for the variables in Table 1, except for Hb A_1c, which was higher among individuals with the –308AA genotype than in those with the GG genotype (P = 0.04; Tukey's post hoc test). FFA was marginally significant for the –238GA polymorphism (P = 0.05), but no differences between the 3 genotypes were observed when Tukey's correction for multiple comparisons was applied. All differences disappeared when individuals with the AA and GA genotypes were combined (Hb A_1c: P = 0.29; FFA: P = 0.07).

View this table: [in this window] [in a new window]   TABLE 1. Clinical and metabolic characteristics and dietary intake by tumor necrosis factor- genotype1

Table 2

View this table: [in this window] [in a new window]   TABLE 2. Association between dietary polyunsaturated fatty acid (PUFA) intake (% of energy) and HDL-cholesterol (mmol/L) or apolipoprotein (apo) A-I (g/L) concentrations for tumor necrosis factor- (TNF-) –238GA and –308GA genotypes1

Table 3

View this table: [in this window] [in a new window]   TABLE 3. Association between dietary polyunsaturated fatty acid (PUFA) intake (% of energy) and HDL-cholesterol concentrations (mmol/L) or apolipoprotein (apo) A-I (g/L) for each combined tumor necrosis factor- (TNF-) genotype1

Figure 1

View larger version (15K): [in this window] [in a new window]   FIGURE 1.. Combined genotypes of tumor necrosis factor- (TNF-) –238GA and –308GA modify the effect of polyunsaturated fatty acids (tertiles of intake – median) on circulating HDL-cholesterol concentrations (P = 0.006 for interaction) and apolipoprotein (apo) A-I (P = 0.04 for interaction). Values are means ± SEMs. Interactions were tested by using a 3 x 3 ANOVA adjusted for sex and BMI (n = 109). The fourth combined genotype with the 2 minor alleles (1/1) is not shown because of the small sample size (n = 7).

We also tested for interactions between TNF- genotypes and dietary PUFA intake on apo A-I concentration, which is a major constituent of the HDL particle. Consistent with the findings for HDL-cholesterol concentrations, interactions were observed between PUFA intake and each TNF- genotype (PUFA x TNF- –238GA, P = 0.02; and PUFA x –308GA, P = 0.001) as well as the combined TNF- genotypes (P = 0.005) on circulating apo A-I concentrations. The interaction was also significant when PUFA was grouped into tertiles of intake (P = 0.02). Interactions remained significant after adjustment for sex and BMI (Tables 2 and 3 and Figure 1).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Our aim was to determine whether TNF- genotypes modify the association between dietary PUFA intake and circulating lipids among individuals with type 2 diabetes. Our results showed that an increased PUFA intake is associated with higher concentrations of HDL cholesterol and apo A-I in subjects with TNF- genotypes that are associated with lower TNF- production. Both n–3 and n–6 PUFAs have been shown to have variable effects on HDL concentrations in humans (1, 29, 30), and our results suggest that genetic factors affecting TNF- production may explain some of these inconsistencies. We did not observe any other significant interactions between TNF- and other fatty acids on circulating lipids. Although the dietary analysis software used in the present study did not distinguish the n–6 from the n–3 fatty acids, we did not expect high intakes of n–3 fatty acids in our study population because these fatty acids are not abundant in the typical Canadian diet (31) and the participants were not residing in coastal cities. Thus, the effects we observed might have been due primarily to the n–6 PUFAs.

High concentrations of TNF- in humans have been associated with low concentrations of circulating HDL cholesterol (5, 13). Several studies have shown that TNF- can independently affect HDL by increasing endothelial lipase (32), decreasing lecithin:cholesterol acyltransferase production and activity (18), and decreasing ATP-binding cassette (ABCA1 and ABCG1) (33), scavenger receptor class B type I (34), and apo A-I and apo A-IV gene expression (16). Each of these proteins tightly regulate the reverse cholesterol transport (35). Furthermore, anti-TNF- therapy given to patients with rheumatoid arthritis causes an increase in HDL concentrations (36).

PUFA can incorporate into membrane phospholipids and activate the transcription nuclear transcription factor B, which regulates the expression of the TNF- gene (37, 38). However, studies relating the effect of PUFAs on TNF- production have shown variable effects. Indeed, both n–3 and n–6 fatty acids have been shown to either increase or decrease TNF- production in humans (6, 7, 9, 39, 40), animals (41–43), and cell culture (44–47). Wallace et al (48) showed that the apparent variable effects of PUFAs on TNF- production could partly be explained by the activation state of the cells and their different capacities to produce prostaglandin E₂ (PGE₂) and leukotriene B₄, which are eicosanoids produced from PUFAs that modulate TNF- production. They found that rats fed a diet supplemented with n–3 fatty acids, and similarly with n–6 fatty acids, had decreased TNF- production in thioglycollate-induced inflammatory macrophages, but increased TNF- production in noninflammatory resident macrophages (48). Therefore, the inflammatory state of the cells, which could be determined by genetic factors, appears to partly influence the effect of PUFAs on TNF- production.

In the present study, increasing PUFA intake was associated with lower concentrations of HDL and apo A-I in individuals with a genotype associated with higher TNF- production, but was associated with higher concentrations of HDL and apo A-I in those with a genotype associated with lower production of the cytokine. The TNF- –238GA polymorphism has been shown to decrease the rate of transcription and production of TNF- (19), whereas the –308GA polymorphism has been shown to increase both (20, 21). Grimble et al (6) showed that, among individuals with the greatest TNF- production, those who were carriers of the TNF- –308A allele had a significantly greater reduction in TNF- production after fish-oil supplementation than did those with the –308GG genotype. It is possible that TNF- polymorphisms cause changes in the production of TNF- on dietary PUFA intake that subsequently modulate the inflammatory state of the cells and affect the reverse cholesterol transport.

The amount of PUFAs consumed also seems to be an important determinant of TNF- production. Renz et al (49) found that PGE₂, which can be derived from PUFAs, stimulated the release of TNF- from rat resident macrophages at lower PGE₂ concentrations but suppressed TNF- release at higher concentrations. However, Trebble et al (39) found that supplementing the diet with n–3 fatty acids at different doses resulted in a U-shaped curve of TNF- production in humans. Therefore, the concentration of the stimulus appears to determine whether TNF- production is enhanced or repressed. In the present study, we showed that the HDL-cholesterol concentration appears to depend not only on the amount of PUFAs consumed, but also on the TNF- genotype of the individual.

PUFAs are natural ligands for the transcription factors PPARs, which have been shown to increase HDL and apo A-I (50, 51). PPARs and TNF- can reciprocally down-regulate each other, such that PPARs decrease TNF- gene expression (52) and TNF- can also decrease the expression of PPARs (15, 53). Thus, high concentrations of PUFAs coupled with high concentrations of TNF- may repress the expression of PPARs and thereby decrease HDL concentrations. However, higher concentrations of PUFAs, if coupled with lower concentrations of TNF-, might preferentially activate PPARs and result in an increase in HDL concentrations. This may explain why an increase in PUFA intake would increase HDL concentrations among individuals with the TNF- genotype associated with lower TNF- production but decrease HDL among those with the genotype associated with higher TNF- production.

In summary, we found that polymorphisms in the promoter region of the TNF- gene alter the association between dietary PUFA and circulating HDL and apo A-I concentrations. Further studies are needed to confirm these results in other populations and to establish the mechanism of action and the type of PUFA (n–3 or n–6) responsible for the effects observed in the present study.

	ACKNOWLEDGMENTS

 
The authors' responsibilities were as follows—TMSW, J-LC, PWC, RGJ, LAL, PM, NWR, EAR, and AE-S: contributed to the study concept, design, and supervision; BF-B and AE-S: drafted the manuscript; BF-B and PNC: carried out the statistical analyses; PWC: provided technical and material support. All authors provided critical revision of the manuscript for important intellectual content. None of the authors had any personal or financial conflicts of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Wijendran V, Hayes KC. Dietary n–6 and n–3 fatty acid balance and cardiovascular health. Annu Rev Nutr 2004;24:597–615.[Medline]
2. Esteve E, Ricart W, Fernandez-Real JM. Dyslipidemia and inflammation: an evolutionary conserved mechanism. Clin Nutr 2005;24:16–31.[Medline]
3. Benatti P, Peluso G, Nicolai R, Calvani M. Polyunsaturated fatty acids: biochemical, nutritional and epigenetic properties. J Am Coll Nutr 2004;23:281–302.[Abstract/Free Full Text]
4. Warne J. Tumour necrosis factor alpha: a key regulator of adipose tissue mass. J Endocrinol 2003;177:351–5.[Abstract]
5. Jovinge S, Hamsten A, Tornvall P, et al. Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism 1998;47:113–8.[Medline]
6. Grimble R, Howell WM, O'Reilly G, et al. The ability of fish oil to suppress tumor necrosis factor alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor alpha production. Am J Clin Nutr 2002;76:454–9.[Abstract/Free Full Text]
7. Caughey G, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n–3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr 1996;63:116–22.[Abstract/Free Full Text]
8. Vega-Lopez S, Kaul N, Devaraj S, Cai RY, German B, Jialal I. Supplementation with omega3 polyunsaturated fatty acids and all-rac alpha-tocopherol alone and in combination failed to exert an anti-inflammatory effect in human volunteers. Metabolism 2004;53:236–40.[Medline]
9. Meydani S, Lichtenstein AH, Cornwall S, et al. Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N–3 fatty acid enrichment. J Clin Invest 1993;92:105–13.[Medline]
10. Ryden M, Arvidsson E, Blomqvist L, Perbeck L, Dicker A, Arner P. Targets for TNF-alpha-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 2004;318:168–75.[Medline]
11. Grunfeld C, Verdier JA, Neese R, Moser AH, Feingold KR. Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo. J Lipid Res 1988;29:1327–35.[Abstract]
12. Van Der Poll T, Romijn JA, Endert E, Borm JJJ, Buller HR, Sauerwein HP. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol 1991;261:E457–65.[Medline]
13. Svenungsson E, Gunnarsson I, Fei GZ, Lundberg IE, Klareskog L, Frostegard J. Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum 2003;48:2533–40.[Medline]
14. Semb H, Peterson J, Tavernier J, Olivecrona T. Multiple effects of tumor necrosis factor on lipoprotein lipase in vivo. J Biol Chem 1987;262:8390–4.[Abstract/Free Full Text]
15. Kim M, Sweeney TR, Shigenaga JK, et al. Tumor necrosis factor and interleukin 1 decrease RXR, PPAR, PPAR, LXR, and the coactivators SRC-1, PGC-1, and PGC-1ß in liver cells. Metabolism 2007;56:267–79.[Medline]
16. Navarro M, Carpintero R, Acin S, et al. Immune-regulation of the apolipoprotein A-I/C-III/A-IV gene cluster in experimental inflammation. Cytokine 2005;31:52–63.[Medline]
17. Duan H, Li Z, Mazzone T. Tumor necrosis factor-alpha modulates monocyte/macrophage apoprotein E gene expression. J Clin Invest 1995;96:915–22.[Medline]
18. Ly H, Francone OL, Fielding CJ, et al. Endotoxin and TNF lead to reduced plasma LCAT activity and decreased hepatic LCAT mRNA levels in Syrian hamsters. J Lipid Res 1995;36:1254–63.[Abstract]
19. Kaluza W, Reuss E, Grossmann S, et al. Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol 2000;114:1180–3.[Medline]
20. Kroeger K, Carville KS, Abraham LJ. The –308 tumor necrosis factor-alpha promoter polymorphism affects transcription. Mol Immunol 1997;5:391–9.
21. Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP. Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies Genes Immun 2000;1:185–90.
22. Hotamisligil G. Inflammation and metabolic disorders. Nature 2006;444:860–7.[Medline]
23. Sniderman A, Blank D, Zakarian R, Bergeron J, Frohlich J. Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula. Clin Biochem 2003;36:499–504.[Medline]
24. Fontaine-Bisson B, Wolever TMS, Chiasson JL, et al. TNF- 238G>A genotype alters post-prandial plasma levels of free fatty acids in obese individuals with type 2 diabetes. Metabolism 2007;56:649–55.[Medline]
25. Health Canada. Canadian nutrient file. Ottawa, Canada: Health Protection Branch, 1997.
26. Kriska A. Modifiable activity questionnaire. In: A collection of physical activity questionnaires for health-related research. Med Sci Sports Exerc 1997;29:S73–8.
27. Barrett J, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21:263–5.[Abstract/Free Full Text]
28. Willet W. Nutritional epidemiology. 2nd ed. New York, NY: Oxford University Press, 1998.
29. Harris W. Fish oil and plasma lipid and lipoprotein metabolism in humans: a critical review. J Lipid Res 1989;30:785–807.[Abstract]
30. Sanders T. Polyunsaturated fatty acids and coronary heart disease. Baillieres Clin Endocrinol Metab 1990;4:877–94.[Medline]
31. Dewailly EE, Blanchet C, Gingras S, et al. Relations between n–3 fatty acid status and cardiovascular disease risk factors among Quebecers. Am J Clin Nutr 2001;74:603–11.[Abstract/Free Full Text]
32. Jin W, Sun GS, Marchadier D, Octtaviani E, Glick JM, Rader DJ. Endothelial cells secrete triglyceride lipase and phospholipase activities in response to cytokines as a result of endothelial lipase. Circ Res 2003;92:644–50.[Abstract/Free Full Text]
33. Khovidhunkit W, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR. J Lipid Res 2003;44:1728–36.[Abstract/Free Full Text]
34. Khovidhunkit W, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Regulation of scavenger receptor class B type I in hamster liver and Hep3B cells by endotoxin and cytokines. J Lipid Res 2001;42:1636–44.[Abstract/Free Full Text]
35. Zannis V, Chroni A, Krieger M. Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. J Mol Med 2006;84:276–94.[Medline]
36. Popa C, Netea MG, Radstake T, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis 2005;64:303–5.[Abstract/Free Full Text]
37. Maziere C, Conte MA, Degonville J, Ali D, Maziere JC. Cellular enrichment with polyunsaturated fatty acids induces an oxidative stress and activates the transcription factors AP1 and NFkappaB. Biochem Biophys Res Commun 1999;265:116–22.[Medline]
38. Epstein F. Nuclear factor-kB—a pivotal transcription factor in chronic inflammatory disease. N Engl J Med 1997;336:1066–71.[Free Full Text]
39. Trebble T, Arden NK, Stroud MA, et al. Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Br J Nutr 2003;90:405–12.[Medline]
40. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n–3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989;320:265–71.[Abstract]
41. Turek J, Schoenlein IA, Clark LK, Van Alstine WG. Dietary polyunsaturated fatty acid effects on immune cells of the porcine lung. J Leukoc Biol 1994;56:599–604.[Abstract]
42. Lokesh B, Sayers TJ, Kinsella JE. Interleukin-1 and tumor necrosis factor synthesis by mouse peritoneal macrophages is enhanced by dietary n–3 polyunsaturated fatty acids. Immunol Lett 1990;23:281–5.[Medline]
43. Rusyn I, Bradham CA, Cohn L, et al. Corn oil rapidly activates nuclear factor-kappaB in hepatic Kupffer cells by oxidant-dependent mechanisms. Carcinogenesis 1999;20:2095–100.[Abstract/Free Full Text]
44. Novak T, Babcock TA, Jho DH, Helton WS, Espat NJ. NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Lung Cell Mol Physiol 2003;284:L84–9.[Abstract/Free Full Text]
45. Zeyda M, Saemann MD, Stuhlmeier KM, et al. Polyunsaturated fatty acids block dendritic cell activation and function independently of NF-kappaB activation. J Biol Chem 2005;280:14293–301.[Abstract/Free Full Text]
46. Tappia P, Man WJ, Grimble RF. Influence of unsaturated fatty acids on the production of tumour necrosis factor and interleukin-6 by rat peritoneal macrophages. Mol Cell Biochem 1995;143:89–98.[Medline]
47. Karsten S, Schafer G, Schauder P. Cytokine production and DNA synthesis by human peripheral lymphocytes in response to palmitic, stearic, oleic, and linoleic acid. J Cell Physiol 1994;161:15–22.[Medline]
48. Wallace F, Miles EA, Calder PC. Activation state alters the effect of dietary fatty acids on pro-inflammatory mediator production by murine macrophages. Cytokine 2000;12:1374–9.[Medline]
49. Renz H, Gong JH, Schmidt A, Nain M, Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol 1988;141:2388–93.[Abstract]
50. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000;49:497–505.[Medline]
51. Fruchart J, Staels B, Duriez P. PPARS, metabolic disease and atherosclerosis. Pharmacol Res 2001;44:345–52.[Medline]
52. Xu J, Chavis JA, Racke MK, Drew PD. Peroxisome proliferator-activated receptor-alpha and retinoid X receptor agonists inhibit inflammatory responses of astrocytes. J Neuroimmunol 2006;176:95–105.[Medline]
53. Tanaka T, Itoh H, Doi K, et al. Down regulation of peroxisome proliferator-activated receptor expression by inflammatory cytokines and its reversal by thiazolidinediones. Diabetologia 1999;42:702–10.[Medline]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fontaine-Bisson, B. Articles by El-Sohemy, A. Search for Related Content PubMed PubMed Citation Articles by Fontaine-Bisson, B. Articles by El-Sohemy, A. Agricola Articles by Fontaine-Bisson, B. Articles by El-Sohemy, A.