Facts on Fats. Ronald P. Mensink

Facts on Fats Ronald P. Mensink Department of Human Biology NUTRIM, School for Nutrition, Toxicology and Metabolism Maastricht University Maastricht The Netherlands

Outline of the Presentation Saturated fatty acids and cardiovascular risk - Stearic acid - Triglyceride structure N-3 polyunsaturated fatty acids Plant stanols Conclusions

Summary on the Effects of Fatty Acids on Fasting Plasma Lipoproteins - compared to carbohydrates - LDL HDL TC/HDL TG SAFA = MUFA cis trans = = PUFA linoleic acid α-linolenic acid EPA/DHA = = =

Two Meta-analyses on Cohort Studies

Two Different Outcomes

What Can We Learn From These Discrepant Findings Observational nutritional epidemiology has its proven benefits, but its limitations should be recognized Rely on randomized clinical trials, if available

Mozaffarian et al. PloS Med, 2010 And What Do RCTs Tell Us?

The Total to HDL Cholesterol Ratio Largely Explains the Effects of (n-6)-pufa vs. SAFA Mozaffarian et al. PloS Med, 2010 RR: 0.91 RR: 0.90 RR decreased when the duration of the study increased

Do (n-6)-pufas Affect Other Non-Lipoprotein Related Pathways? Systemic inflammation Blood pressure Endothelial function Haemostatic function Mixed results Insulin resistance Postprandial metabolism Weight gain

What Is the Best Fasting Lipid Marker to Define Cardiovascular Risk? The options: LDL cholesterol HDL cholesterol Triacylglycerol The total to HDL cholesterol ratio

What Is the Best Fasting Lipid Marker to Define Cardiovascular Risk? The options: LDL cholesterol HDL cholesterol Triacylglycerol The total to HDL cholesterol ratio For diet-induced changes: comparable risk estimates Total to HDL cholesterol is the most simple one

Effects of Different Classes of Fatty Acids on Total to HDL Cholesterol 0.04 0.02 0-0.02-0.04 Change * * * Total to HDL cholesterol SAFA Cis-MUFA Cis-PUFA Trans-MUFA Relative to carbohydrates SAFA do not Cis-MUFA favorably Cis-PUFA favorably Trans-MUFA adversely change the total:hdl cholesterol ratio Effects of trans-mufa is about 7.3 as strong as that of SAFA

Effects on CHD-risk of Consuming 5 En% of the Different FA in place of Carbohydrates 0.2 Change 6 % Change 0.1 3 0 0-3 -0.1-6 -0.2 Total to HDL cholesterol -9 CHD-risk SAFA Cis-PUFA Cis-MUFA Trans-MUFA

Effects of Individual Saturated Fatty Acids on Total to HDL Cholesterol 0.01 0-0.01-0.02 Change Relative to carbohydrates C12:0 (lauric acid) favorably affects the total to HDL cholesterol ratio -0.03-0.04 * Total to HDL cholesterol SAFA C12:0 C14:0 C16:0 C18:0 C14:0 (myristic acid) C16:0 (palmitic acid) C18:0 (stearic acid) have no effects

Effects on CHD-risk of 5 En% of the Individual Saturated FA in Place of Carbohydrates 0.05 Change 2 % Change 0.00 0-0.05-2 -4-0.10-6 -0.15-8 -0.20-10 Total to HDL cholesterol CHD-risk SAFA C12:0 C14:0 C16:0 C18:0

Fatty Acids and Plasma Markers of Inflammation and Endothelial Function Fibrinogen CRP IL-6 E-selectin CHO OL TFA TFA+STE STE LMP Baer et al. Am J Clin Nutr, 2004 FA exchange: 8 En%

Effects on CHD-risk of 5 En% of C18:0 and Trans-MUFA 6 % Change 0 % Change 3-3 0-6 -3 CHD-risk -9 CHD-risk Compared to carbohydrates Replacement of TFA with C18:0 C18:0 Trans-MUFA

Interesterification Interesterification: re-arrangement of fatty acids over the triacylglycerol molecule Change in physical characteristics Interesterification can be used as an alternative to partial hydrogenation

Structure of Triacylglycerol from Vegetable Oils Sn-1:Mainly (mono-un)saturated Sn-2: Mainly polyunsaturated Sn-3: Mainly (mono-un)saturated

Why Should We Care About the Positional Distribution of Fatty Acids?

Metabolism The sn-2 fatty acid is largely preserved, which may have metabolic consequences The sn-1 and sn-3 free saturated fatty acids may form calcium soaps in the GI tract delayed or decreased absorption

Possible Differential Effects of Natural vs. Semisynthetic Fats is Not New

Grande et al. Am J Clin Nutr, 1970... But Controversial

Interesterification Does not Change the Effects of Fats on Serum Lipids Palmitic acid - Nestel et al. (Am J Clin Nutr 1995; 62:950-5) - Zock et al. (Am J Clin Nutr 1995; 61:48-55) Stearic acid - Grande et al. (Am J Clin Nutr 1970; 23:1184-93) - Berry et al. (Am J Clin Nutr 2007; 85:1486-94)

Effects of Interesterified Fat Blends on Fasting Serum Lipids are Highly Controversial Meijer and Weststrate (Eur J Clin Nutr 1997; 51: 527-34) - Native vs. interesterified mixed fat blend providing 4 or 8 En%. - 60 healthy normocholesterolemic men and women - 21 days on diet (cross-over design) No effects on the serum lipoprotein profile

Effects of Interesterified Fat Blends on Fasting Serum Lipids are Highly Controversial Sundram et al. (Nutr Metab 2007;4:3) - Palm olein vs. partially hydrogenated soy bean oil vs. an interesterified fat rich in stearic acid providing > 70% of total fat intake. - Total fat intake was 31 En%. - 30 healthy normocholesterolemic men and women - 28 days on diet (cross-over design) An interesterified fat rich in stearic acid has adverse effects on LDL cholesterol

Test Fats Palm olein Partially hydrogenated soybean oil (PHSO) Interesterified fats (IE) rich in stearic acid - Fully hydrogenated soybean oil - Blended with soybean oil and palm olein - Interesterification Sundram et al. Nutr Metab, 2007

Intakes of Fatty Acids 20 15 En% 10 5 0 Palm olein PHSO Interesterified fat Sundram et al. Nutr Metab, 2007 SAFA C16:0 C18:0 MUFA PUFA Trans

Predicted vs. Observed Effects of the Fats on LDL and HDL Cholesterol 0.30 0.20 mmol/l * mmol/l 0.00 0.10 0.00-0.05-0.10-0.20-0.30-0.40 LDL cholesterol -0.10-0.15 * HDL cholesterol * Compared to Palm Olein: Sundram et al. Nutr Metab, 2007 Predicted PHSO Observed PHSO Predicted IE Observed IE

Conclusions about Saturated Fatty Acids Consumption of (n-6)-polyunsaturated fatty acids in place of a mixture of saturated fatty acids lowers cardiovascular risk Effects of other macronutrients largely unknown Stearic acid and interesterification may be suitable alternatives for trans monounsaturated fatty acids (but more research is needed )

Outline of the Presentation Saturated fatty acids and cardiovascular risk - Stearic acid - Triglyceride structure N-3 polyunsaturated fatty acids Plant stanols Conclusions

What About n-3 or ω-3 Fatty Acids - structures, dietary intakes - CH3 3 first double bond in n-3 or omega-3 position COOH Alpha-linolenic acid (ALA, C18:3n-3) Intake from plant oils 1-2 g/day 3 CH3 Eicosapentaenoic acid (EPA, C20:5n-3) 3 COOH COOH Intake from fish 0.1-0.2 g/day CH3 Docosahexaenoic acid (DHA, C22:6n-3)

Conversion of Linolenic Acid into DHA 6 desaturation Elongation 5 desaturation Elongation Elongation 6 desaturation β-oxidation 18:3(n-3) Linolenic acid (ALA) 20:5(n-3) EPA 22:5(n-3) DPA 22:6(n-3) DHA

Can -Linolenic Acid Replace Fish Oil? -Linolenic acid cannot replace fish oil

Can -Linolenic Acid Replace Fish Oil? ALA and EPA / DHA have different metabolic effects Conversion of α-linolenic acid into EPA is low: <10% Conversion of EPA into DHA is even lower: <1% Conversion of ALA into EPA is slightly inhibited by linoleic acid The ALA/LA ratio is not important Do not use the n-3 / n-6 ratio for dietary recommendations

n-3 Fatty Acids and Cardiovascular Disease Outcomes - a systematic review - Wang et al. Am J Clin Nutr, 2006

Relative Risk of Fatal MI Might Be Lower in Men with a High α-linolenic Acid Intake Dolocek & Granditis 1991 Ascherio et al. 1996 Pietinen et al. 1997 Hu et al. 1999 Oomen et al. 2001 Combined RR Brouwer et al. J Nutr, 2004 0.3 0.4 0.5 0.65 0.8 1 1.2 1.5 2.0 2.7 3.5 4.5

The Debate on n-3 Fatty Acids and Cardiovascular Disease Will Continue Kromhout et al. (New Engl J Med, August 29, 2010) 4837 patients (60-80 yrs), who had had a myocardial infarction and received good clinical care For 40 months, additional daily intake of 1.9 g ALA OR 376 mg EPA/DHA Conclusion: Low doses of n-3 fatty acids did not reduce cardiovascular endpoints

Why Do Fish Oil FA Have Beneficial Effects on Cardiovascular Disease? Lower serum triglycerides Lower blood pressure Decrease platelet aggregation Improve endothelial function? Are anti-inflammatory? Are anti-arrhythmic

Flaxseed Does not Increase (n-3)-lcpufa Status in Human Myocardial Phospholipids 25 % 20 15 n-3 FA intake: 5-6 g 9 % 6 10 3 5 0 0 C20:4(n-6) C18:3 C20:5 C22:6 Olive oil (28 d) Flaxseed (29 d) Fish oil (33 d) Metcalf et al. Am J Clin Nutr, 2007

The Omega-3 Index as a Risk Marker for Death from Coronary Heart Disease Introduced by Harris and colleagues The sum of EPA+DHA in red blood cells >8% greatest cardioprotection <4% least cardioprotection To reach an omega-3 index of 8%, the intake of EPA/DHA should be at least 1 g (but probably higher)

Effects of Linolenic Acid and EPA/DHA on the Omega-3 index 6 * Omega-3 index 4 2 Run-in period of 4 weeks Intervention period of 24 weeks 10-12 subjects in each group Additional ALA intake: 3.3 gram Additional EPA/DHA intake: 0.6 gram 0 Control ALA-group EPA/DHA group Mensink, Unpublished results

Conversion of Linoleic Acid and Linolenic 18:2(n-6) Linoleic acid (LA) 20:4(n-6) AA 22:4(n-6) 22:5(n-6) Acid into LCPUFAs 6 desaturation (FADS2) Elongation 5 desaturation (FADS1) Elongation Elongation 6 desaturation (FADS2) β-oxidation 18:3(n-3) Linolenic acid (ALA) 20:5(n-3) EPA 22:5(n-3) DPA 22:6(n-3) DHA

FADS1 FADS2 Gene Variants Relate to LCPUFA Levels - Results from the KOALA Birth Cohort Study - Fatty acid composition was determined in week 34 of pregnancy and in milk 1 month postpartum For 309 women, 3 SNPs from the FADS1 FADS2 gene cluster were analyzed: rs174561, rs3834458, rs174575 The SNPs were highly linked FFQ were determined in week 34 of pregnancy Genotype was not related to fatty acid intake

The n-6 FA Profile in Plasma and Human Milk is Related to FADS1 Genotype 25 % 20 C18:2(n-6) LA 8 % 6 C20:4(n-6) AA 4 15 2 P<0.001 P<0.001 P<0.001 P<0.001 10 0 Plasma Human milk Plasma Human milk (*10) MM, n=166 Mm, n=125 mm, n=18 Molto-Puigmarti et al. Am J Clin Nutr, 2010 rs174561: FADS1

The DHA Level in Plasma and Human Milk is Related to FADS1 Genotype 0.6 % 0.4 C20:5(n-3) EPA 4 % 3 C22:6(n-3) DHA 2 0.2 P=0.580 P=0.083 P=0.002 P=0.044 1 0.0 0 Plasma Human milk Plasma Human milk Molto-Puigmarti et al. Am J Clin Nutr, 2010 MM, n=166 Mm, n=125 mm, n=18 rs174561: FADS1

Relation between Fish Intake and DHA in Human Milk Relates to FADS Gene Variants Molto-Puigmarti et al. Am J Clin Nutr, 2010 MM, n=168 Mm, n=126 mm, n=15 rs174575: FADS2

Conclusions about (n-3) Polyunsaturated Fatty Acids α-linolenic cannot replace EPA / DHA Do not use the n-3 / n-6 ratio The usefulness of the Omega-3 Index needs to be proven FADS genotype variants are important determinants of LCPUFA levels. Studies with functional outcomes are needed

Outline of the Presentation Saturated fatty acids and cardiovascular risk - Stearic acid - Triglyceride structure N-3 polyunsaturated fatty acids Plant stanols Conclusions

Plant Sterols / Stanols Have a Structure Very Similar to that of Cholesterol HO HO Cholesterol Sitosterol HO Sitostanol R Sitostanol ester

Questions Do effects of plant stanols on LDL cholesterol level off at intakes? Do plant stanols only affect LDL cholesterol? A large proportion of the populations has high TAG and low HDL cholesterol concentrations

Plant Stanol Esters Decrease LDL Cholesterol Dose-Dependently mmol/l % LDL cholesterol 3-g group LDL cholesterol 6-g group 9-g group Mensink et al. Am J Clin Nutr, 2010

In Subjects with the Metabolic Syndrome, Plant Stanols Lower Serum Triacylglycerol 2.5 mmol/l 0.3 mmol/l 2.0 0.2 1.5 1.0 0.1 0-0.1 27% reduction by plant stanols versus control 0.5-0.2 0.0-0.3 Baseline Change Control Plant stanols (8 weeks, 2 g plant stanols / day as a yogurt drink) Plat et al. J Nutr, 2010

Conclusions about Plant Stanols Plant stanols lower serum LDL cholesterol dosedependently at intakes up to 9 g Plant stanol esters may lower serum triacylglycerol concentrations, especially in subjects with elevated baseline serum triacylglycerol concentrations This effect most likely origins from a lowered hepatic production of large TAG-rich VLDL particles

Outline of the Presentation Saturated fatty acids and cardiovascular risk - Stearic acid - Triglyceride structure N-3 polyunsaturated fatty acids Plant stanols Conclusions

Basis of Dietary Guidelines for Healthy Adults 1. Fat is not necessarily bad, but fatty acids can be bad SAFA can be replaced by cis-(poly)unsaturated fatty acids (though fat intake should not be unlimited) 2. Functional foods can be helpful 3. There is more than just fat

Basis of Dietary Guidelines for Healthy Adults Saturated and trans fatty acids Cardiovascular disease Polyunsaturated fatty acids Essential fatty acids Cardiovascular disease Total fat intake Essential fatty acids, vitamins, energy Insulin resistance, energy intake??

Thank You Very Much for Your Kind Attention!