식이 지방에 의한 면역 및 염증 반응 조절 Sung Nim Han, Ph.D., RD. Seoul National University Department of Food and Nutrition

Trends in dietary fat consumption Korean (1971)Korean (2005) Energy (kcal) Dietary Fat (%) 20.2 Dietary Fat (g) Animal Fat (g) 20.5 NHANES ( ) NHANES ( ) Energy (kcal)2450 (M)/1542(F)2618(M)/1877(F) Dietary Fat (%)36.9(M)/36.1(F)32.8(M)/32.8(F)

COOH H3CH3C H3CH3C H3CH3C Stearic acid18:0 Oleic acid 18:1  -9 Linoleic acid 18:2  -6  - Linolenic acid18:3  -3 H3CH3C COOH Fatty acid structure and nomenclature

Dietary Fat and Immune Response  Both quantity and quality of dietary fat affect immune response: – Amount of fat and cholesterol in the diet – Degree of saturation – Types of PUFA : n-6 vs. n-3

 Eicosanoid production (PGE 2 )  Cell signaling pathway  Membrane physiology (microviscosity)  Lipid Raft assembly and function Dietary Fat and Immune Response: Mechanisms

Journal of Lipid Research 2003;44:2304

Study Design  Subjects Men and women over the age of 50 yrs with moderately elevated LDL cholesterol levels (>130 mg/dL)  Study Design Double-blind Experimental diets in randomized order for periods of 32 days each Han et al. J Lipid Res 2003;44:2304

Characteristics of the Subjects at Baseline CharacteristicsWomenMenAll Subjects Age (Years) BMI (kg/m2) Total Chol. (mg/dL) VLDL Chol (mg/dL)31 LDL Chol (mg/dL) HDL Chol (mg/dL) Triglyceride (mg/dL) Han et al. J Lipid Res 2003;44:2304

Methods  DTH Multi-Test CMI with 7 recall antigens  Lymphocyte Proliferation PBMC stimulated with PHA or Con, measured by 3 H-thymidine incorporation  IL-2 Activity PBMC stimulated with PHA or ConA, measured by Bioassay  PGE 2 Production PBMC stimulated with PHA, measured by RIA  IL-1, IL-6, and TNF-  Production PBMC stimulated with LPS, measured by ELISA Han et al. J Lipid Res 2003;44:2304

Experimental Diets  Western Diet: –38% Fat (16% SFA, 15% MUFA, 7% PUFA) –17% Protein –45% Carbohydrate –164 mg cholesterol per 1000kcal  TLC Diet: –28% Fat (7% SFA, 8%MUFA, 13%PUFA) –16% Protein –56% Carbohydrate –66 mg cholesterol per 1000kcal Han et al. J Lipid Res 2003;44:2304

Consumption of TLC diet increases DTH response compared with Western Diet * Significantly different from Western Diet at p<0.05 Han et al. J Lipid Res 2003;44:2304 *

Consumption of TLC diet increases Lymphocyte Proliferative Response Compared with Western Diet * Significantly different from Western Diet at p<0.05 Han et al. J Lipid Res 2003;44:2304

Effects of TLC diet on lymphocyte subpopulation Diet Lymphocyte SubpopulationWesternTLC CD3+ (T cells) CD4+ (helper T cells) CD8+ (cytotoxic T cells) CD19+ (B cells) Han et al. J Lipid Res 2003;44:2304

Effects of TLC diet on serum lipid profile Serum lipidWesternTLC Total Chol (mg/dL) * VLDL Chol (mg/dL) 2833 LDL Chol (mg/dL) * HDL Chol (mg/dL) 4744* Triglyceride (mg/dL) * Total Chol/HDL Chol Ratio * P<0.05 determined by paired t-test Han et al. J Lipid Res 2003;44:2304

Journal of Lipid Research 2002;43:445

Experimental Diets Diet ConstituentButterStick Margarine Soybean Oil Protein16.9 % energy Carbohydrate Fat SFA MUFA PUFA Trans Cholesterol (mg/1,000kcal) Han et al. J Lipid Res 2002;43:445

Trans Fatty Acid  High intake of hydrogenated fat has been shown to result in unfavorable LDL and HDL cholesterol levels and to be associated with a higher risk of CHD.  Only few studies have investigated the effects of trans fatty acids on the immune function, none of which were conducted in humans.

Consumption of fat high in trans fatty acid increases production of TNF-  * Means not sharing the same letters are significantly different at p<0.05 ab a b Han et al. J Lipid Res 2002;43:445

Consumption of fat high in trans fatty acid increases production of IL-6 ab a b * Means not sharing the same letters are significantly different at p<0.05 Han et al. J Lipid Res 2002;43:445

Role of TNF-  and IL-6 in Atherosgenesis  TNF-  – Promotes monocyte adhesion – Induces macrophage differentiation – Promotes foam cell formation – Stimulates growth of smooth muscle cells  IL-6 – Increases the release of adhesion molecules – Has procoagulant effects on platelet – Inhibits lipoprotein lipase and stimulates lipolysis

 The association of trans fatty acid and inflammatory response has been demonstrated in epidemiological studies. – Trans fatty acid levels in red blood cell membrane was positively associated with IL-1 , IL-6, TNF- , and IL-10 in 86 patients with established heart disease. (Mozaffarian et al. AJCN 2004; 80:1521)

 The association of trans fatty acid and inflammatory response has been demonstrated in epidemiological studies. Dietary intake of trans fatty acids and systemic inflammation in women Dariush Mozaffarian, Tobias Pischon, Susan E Hankinson, Nader Rifai, Kaumudi Joshipura, Walter C Willett, and Eric B Rimm AJCN 2004; 79:606 – Dietary intake of trans fatty acid was positively associated with sTNF-R1 and sTNF-R2 in 823 generally healthy women, and positively associated with IL-6 and CRP in women with higher BMI.

Am J Clin Nutr 2004; 79:969 N Engl J Med 2006; 354:1601

Effect of Different Dietary Fats on DTH Response a ab b * Means not sharing the same letters are significantly different at p<0.05 Han et al. J Lipid Res 2002;43:445

Effects of different dietary fats on serum lipid profile Serum lipidButter Stick margarine Soybean oil Total Chol (mg/dL)257 a 245 b 227 c VLDL Chol (mg/dL)32 b 36 a 32 ab LDL Chol (mg/dL)177 a 167 b 150 c HDL Chol (mg/dL)48 a 42 c 45 b Triglyceride (mg/dL) Total Chol/HDL Chol Ratio 5.55 b 6.00 a 5.28 b Values not sharing the same letters are significantly different at P<0.05 Han et al. J Lipid Res 2002;43:445

Conclusion  Consumption of a low-fat diet in accordance with a TLC diet, compared with a Western high-fat diet, improves T cell-mediated immune response.  Higher production of inflammatory cytokine, TNF-  and IL-6, after consumption of a diet containing hydrogenated fat, may contribute to the reported atherogenic effect of these diets. Han et al. J Lipid Res 2002;43:445

COOH CH 3 COOH CH 3 COOH CH 3 Structural formulas for n-6 and n-3 fatty acids Arachidonic acid (20:4 n6) Eicosapentaenoic acid (20:5 n3) Linoleic acid (18:2 n6) COOH CH 3  -linolenic acid (18:3 n3)

16:018:0 18:1n-9 Acetyl-CoA 18:2n-6 18:3n-6 18:3n-3 18:4n-3 20:4n-320:3n-6 22:4n-6 20:4n-6 22:4n-6 20:5n-3 22:5n-3 22:6n-3 Δ6 desaturase Elongase Δ5 desaturase Δ4 desaturase Δ12 desaturase (plants only) Δ9 desaturase Δ15 desaturase (plants only) Diet or de novo synthesis Diet Biosynthesis of polyunsaturated fatty acids 16:1n-7 n-9 PUFA n-7 PUFA (EPA) (DHA) (Arachidonic acid)

Membrane Phospholipid Arachidonic Acid Phopholipase A 2 PGG 2 5-HPETE12-HPETE15-HPETEPGH 2 Cyclooxygenase 5-Lipoxygenase 12-Lipoxygenase 15-Lipoxygenase Cyclooxygenase activity Peroxidase activity 5-HETELeukotriens (LTB 4, LTE 4 ) Prostaglandins & Prostacyclins (PGE 2, PGI 2 ) TXA 2 12-HETE15-HETE LipoxinA 4 3 series Prostaglandins & Prostacyclins (PGE 3, PGI 3 ) are produced with long-chain n-3 fatty acids TXA 3 produced with long- chain n-3 fatty acids 5 series Leukotriens (LTB 5, LTE 5 ) are produced with long-chain n-3 fatty acids

ARACHIDONIC ACID 4-Series LT Inflammation EPA 3-Series PG5-Series LT Less inflammation 2-Series PG replace

Impact of Soybean Oils varying in Fatty Acid Profile on T cell Proliferation of Moderately Hyperlipidemic Subjects Sung Nim Han, Alice H Lichtenstein, Di Wu, Lynne M Ausman, Simin Nikbin Meydani Han et al. FASEB J 2006; 20:A123.

Objective of the Study To investigate the effects of feeding selectively bred and genetically modified soybean oils with distinguished fatty acid profiles, resulting in varied linoleic/linolenic acids ratios, on immune response of adults with moderately elevated plasma cholesterol concentration. Han et al. FASEB J 2006; 20:A123.

Conclusion Consumption of diets containing different types of soybean oils with distinguished fatty acid profiles had significant impact on proliferative response of lymphocytes. An inverse correlation between proliferative response and linoleic/linolenic acid ratio was present. Optimal proliferative response was observed at linoleic/linolenic acid ratio of 8.5. Han et al. FASEB J 2006; 20:A123.

Acknowledgements  Nutritional Immunology Laboratory – Dr. Simin Nikbin Meydani – Lynette S. Leka – Dr. Dayong Wu – Dr. Michael Hayek – Dr. Alison Beharka – Faria Eksir – Adam Thomas – Dr. Oskar Adolfsson – Dr. Raina Gay – Dr. Melissa Marko – Sarah Belisle – MunKyong Pae  Cardiovascular Nutrition Laboratory – Dr. Alice H Lichtenstein – Dr. Lynne M Ausman – Susan Jalbert  Dr. Gerald Dallal

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