Sung Nim Han Ph D RD Seoul National

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식이 지방에 의한 면역 및 염증 반응 조절 Sung Nim Han, Ph. D. ,

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 Energy (kcal) Korean (1971) Korean (2005) 2072 2016 Dietary

Trends in dietary fat consumption Energy (kcal) Korean (1971) Korean (2005) 2072 2016 Dietary Fat (%) Dietary Fat (g) 20. 2 13. 1 Animal Fat (g) Energy (kcal) Dietary Fat (%) 46 20. 5 NHANES (1971 -74) (1999 -2000) 2450 (M)/1542(F) 2618(M)/1877(F) 36. 9(M)/36. 1(F) 32. 8(M)/32. 8(F)

Fatty acid structure and nomenclature H 3 C COOH 9 H 3 C COOH

Fatty acid structure and nomenclature H 3 C COOH 9 H 3 C COOH 18: 0 Stearic acid 18: 1 w-9 Oleic acid 18: 2 w-6 Linoleic acid 18: 3 w-3 a-Linolenic acid H 3 C 6 H 3 C 3 COOH

www. ag. ndsu. edu/pubs/yf/foods/fn 620 -1. gif

www. ag. ndsu. edu/pubs/yf/foods/fn 620 -1. gif

Dietary Fat and Immune Response § Both quantity and quality of dietary fat affect

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

Dietary Fat and Immune Response: Mechanisms § Eicosanoid production (PGE 2) § Cell signaling

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

Journal of Lipid Research 2003; 44: 2304

Journal of Lipid Research 2003; 44: 2304

Study Design § Subjects Men and women over the age of 50 yrs with

Study Design § Subjects Men and women over the age of 50 yrs with moderately elevated LDL cholesterol levels (>130 mg/d. L) § 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 Characteristics Women Men Age (Years) 67 61 All

Characteristics of the Subjects at Baseline Characteristics Women Men Age (Years) 67 61 All Subjects 65 BMI (kg/m 2) 28 30 29 Total Chol. (mg/d. L) 251 255 253 VLDL Chol (mg/d. L) 31 31 31 LDL Chol (mg/d. L) 164 180 171 HDL Chol (mg/d. L) 56 44 51 Triglyceride (mg/d. L) 153 156 154 Han et al. J Lipid Res 2003; 44: 2304

Methods § DTH Multi-Test CMI with 7 recall antigens § Lymphocyte Proliferation PBMC stimulated

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 Con. A, measured by Bioassay § PGE 2 Production PBMC stimulated with PHA, measured by RIA § IL-1, IL-6, and TNF-a 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,

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

Consumption of TLC diet increases DTH response compared with Western Diet * * Significantly

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

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 Subpopulation Western TLC CD 3+

Effects of TLC diet on lymphocyte subpopulation Diet Lymphocyte Subpopulation Western TLC CD 3+ (T cells) 72. 6 + 3. 0 71. 9 + 2. 3 CD 4+ (helper T cells) 47. 0 + 2. 2 45. 9 + 1. 7 CD 8+ (cytotoxic T cells) 20. 1 + 2. 0 18. 8 + 1. 7 CD 19+ (B cells) 8. 2 + 0. 7 8. 2 + 1. 0 Han et al. J Lipid Res 2003; 44: 2304

Effects of TLC diet on serum lipid profile Serum lipid Western TLC Total Chol

Effects of TLC diet on serum lipid profile Serum lipid Western TLC Total Chol (mg/d. L) 249 228* VLDL Chol (mg/d. L) 28 33 LDL Chol (mg/d. L) 168 151* HDL Chol (mg/d. L) 47 44* Triglyceride (mg/d. L) 137 163* Total Chol/HDL Chol Ratio 5. 44 5. 35 * P<0. 05 determined by paired t-test Han et al. J Lipid Res 2003; 44: 2304

Journal of Lipid Research 2002; 43: 445

Journal of Lipid Research 2002; 43: 445

Experimental Diets Diet Constituent Butter Stick Margarine Soybean Oil Protein 16. 9 % energy

Experimental Diets Diet Constituent Butter Stick Margarine Soybean Oil Protein 16. 9 % energy 16. 7 Carbohydrate 54. 0 53. 5 55. 8 Fat 29. 1 29. 7 28. 5 SFA 16. 7 8. 5 7. 3 MUFA 8. 1 8. 5 8. 1 PUFA 2. 4 6. 3 12. 6 Trans 1. 3 6. 7 0. 6 Cholesterol (mg/1, 000 kcal) 121 67 66 15. 7 Han et al. J Lipid Res 2002; 43: 445

Trans Fatty Acid § High intake of hydrogenated fat has been shown to result

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-a a ab

Consumption of fat high in trans fatty acid increases production of TNF-a 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

Consumption of fat high in trans fatty acid increases production of IL-6 ab a

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-a and IL-6 in Atherosgenesis § TNF-a Promotes monocyte adhesion – Induces

Role of TNF-a and IL-6 in Atherosgenesis § TNF-a 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

§ 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 b, IL-6, TNF-a, 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

§ 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 s. TNF-R 1 and s. TNF-R 2 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

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

Effect of Different Dietary Fats on DTH Response b ab a * Means not

Effect of Different Dietary Fats on DTH Response b ab a * 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 Butter Stick margarine Soybean oil

Effects of different dietary fats on serum lipid profile Butter Stick margarine Soybean oil Total Chol (mg/d. L) 257 a 245 b 227 c VLDL Chol (mg/d. L) 32 b 36 a 32 ab LDL Chol (mg/d. L) 177 a 167 b 150 c HDL Chol (mg/d. L) 48 a 42 c 45 b Triglyceride (mg/d. L) 153 166 158 Total Chol/HDL Chol Ratio 5. 55 b 6. 00 a 5. 28 b Serum lipid 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

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, TNFa 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

Structural formulas for n-6 and n-3 fatty acids Linoleic acid (18: 2 n 6)

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

Biosynthesis of polyunsaturated fatty acids n-7 PUFA 16: 1 n-7 Acetyl-Co. A 16: 0

Biosynthesis of polyunsaturated fatty acids n-7 PUFA 16: 1 n-7 Acetyl-Co. A 16: 0 18: 0 Δ 9 desaturase Diet or de novo synthesis 18: 1 n-9 PUFA Diet Δ 12 desaturase (plants only) 18: 2 n-6 18: 3 n-3 Δ 15 desaturase (plants only) Δ 6 desaturase 18: 3 n-6 18: 4 n-3 Elongase 20: 3 n-6 20: 4 n-3 Δ 5 desaturase (Arachidonic acid) 20: 4 n-6 20: 5 n-3 Elongase 22: 4 n-6 22: 5 n-3 (EPA) 22: 6 n-3 (DHA) Δ 4 desaturase 22: 4 n-6

Membrane Phospholipid Phopholipase A 2 Arachidonic Acid Cyclooxygenase activity 5 -Lipoxygenase 12 -Lipoxygenase PGG

Membrane Phospholipid Phopholipase A 2 Arachidonic Acid Cyclooxygenase activity 5 -Lipoxygenase 12 -Lipoxygenase PGG 2 Peroxidase activity PGH 2 Prostaglandins & Prostacyclins (PGE 2, PGI 2) 3 series Prostaglandins & Prostacyclins (PGE 3, PGI 3) are produced with long -chain n-3 fatty acids 5 -HPETE TXA 2 TXA 3 produced with longchain n-3 fatty acids 5 -HETE Leukotriens (LTB 4, LTE 4) 5 series Leukotriens (LTB 5, LTE 5) are produced with long-chain n-3 fatty acids 15 -Lipoxygenase 12 -HPETE 12 -HETE 15 -HPETE 15 -HETE Lipoxin. A 4

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

replace ARACHIDONIC ACID 2 -Series PG 4 -Series LT Inflammation EPA 3 -Series PG 5 -Series LT Less inflammation

Impact of Soybean Oils varying in Fatty Acid Profile on T cell Proliferation of

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: A 123.

Objective of the Study To investigate the effects of feeding selectively bred and genetically

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: A 123.

Conclusion Consumption of diets containing different types of soybean oils with distinguished fatty acid

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: A 123.

Acknowledgements § Nutritional Immunology Laboratory § Dr. Simin Nikbin Meydani – Lynette S. Leka

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

Thank You!

Thank You!