Clinical and Health Affairs
Trans Fats
Foods, Facts, and Biology
By So Young Bu, Ph.D., and Douglas G. Mashek, Ph.D.
Abstract
Trans fatty acids (TFAs) have made headlines because of the federal government’s recent regulatory steps to reduce dietary intake of these potentially dangerous compounds. This review will focus on the chemistry of TFAs, their dietary sources, their association with various chronic diseases, and the possible mechanisms explaining their biological effects.
In 2006, the term “trans fatty acid” (TFA) entered the public’s vocabulary. On January 1 of that year, the Food and Drug Administration implemented a rule requiring all food labels to include TFA content if the item contains more than 0.5 g per serving. That December, New York City became the first city in the United States to ban TFAs in foods served in restaurants. Since that time, dozens of cities throughout the country and, most recently, the state of California have passed similar legislation, with others proposing such bans. Around the world, many countries have or are pursuing bans on TFAs, including Denmark, which in 2003 became the first country to ban the sale of foods containing industrially produced TFAs in both restaurants and grocery stores.
What are Trans Fatty Acids?
Dietary fats and oils are a combination of numerous fatty acids. These fatty acids have unique structures and, as a result, possess distinct physical and biological properties. For instance, saturated fatty acids, which have a high melting point, are more stable than mono or polyunsaturated fatty acids in terms of storage and handling, but they increase the risk of diseases including atherosclerosis, diabetes, and cancer. In contrast, unsaturated fatty acids typically have favorable effects on health but are much less stable than saturated fatty acids.
Trans fat is the common name for a type of unsaturated fat with trans-isomer fatty acids. By definition, TFAs contain at least 1 double bond in the trans configuration in contrast to naturally occurring unsaturated fatty acids, which have the cis configuration at their double bonds (Figure).1 Trans fats may be monounsaturated or polyunsaturated. They are primarily derived from hydrogenation of vegetable oils but are naturally occurring in some ruminant animals such as cows and sheep. Partial hydrogenation of unsaturated fatty acids decreases the number of double bonds and rearranges the double bonds by converting some of them to the trans configuration. The trans configuration of fat raises its melting point, thereby enhancing its stability for handling and storage.2 TFAs have historically been used in food as an alternative to saturated fatty acids because of their stability, which is important to the shelf life of processed food and the retardation of frying oil rancidity.3 Elaidic acid (C18:1trans-9) is the predominant isomer of industrially produced TFAs; more than 60% of TFAs in ruminants are trans-vaccenic acid (C18:1trans-11).2,4
Sources of Dietary Trans Fatty Acids
Foods that have been major contributors to TFA intake include margarines (1.16% to 7.84% TFA content per weight basis); snacks such as biscuits, cakes, and popcorn (5% to 10%); and frying oils (23% to 30%).5,6 Because of recent concern about the health effects of consuming trans fats, many commercial food producers are reducing the amount of trans fats in their products. Trans fatty acids in fast foods and snacks can comprise up to 50% of a person’s daily fat intake, with some people ingesting as many as 36 g of trans fat in a single meal, according to an analysis of fast food from McDonalds and KFC outlets in 20 countries.5 Researchers found that French fries and fried chicken from these restaurants contain the highest amount of TFAs (8.8 g to10 g per large serving).
According to the FDA, the average daily intake of TFAs is about 5.8 g per day (2.6% of calories) for individuals 20 years of age and older in the United States.1 There is no recommended limit on TFA consumption, and the average consumption may be decreasing. Using data from the Minnesota Heart Survey, Harnack et al. estimated that TFA consumption expressed as a percentage of total energy intake was 3% in 1980-82, 2.8% in 1985-87, 2.5% in 1990-92, and 2.2% in 1995-97.7 A further decline in intake is expected to occur with the FDA’s labeling requirements for TFAs, the increasing number of bans on TFA usage by restaurants, and growing consumer awareness of the undesirable health effects of consuming TFAs.
TFAs and Disease Risk
One reason why cities, states, and even countries have banned the use of TFAs by restaurants is because they have been linked to debilitating conditions including coronary heart disease (CHD), type 2 diabetes, and cancer. Such diseases not only affect morbidity and mortality but also contribute to increasing health care costs.
♦ Coronary Heart Disease
Trans fatty acid intake has a strong positive association with CHD.8 The Nurses’ Health Study, which involves nearly 80,000 women in the United States, found a 33% increase in the incidence of CHD among those participants in the highest quintile of TFA intake compared with those in the lowest quintile.9 Mozaffarian and colleagues conducted a meta-analysis of 4 prospective cohort studies involving 140,000 subjects and noted that a 2% increase in energy intake from TFAs was associated with a 23% increase in the risk of CHD.10 Studies using biomarkers have also shown a strong positive correlation between risk for CHD and tissue concentration of TFAs.11-13 For example, TFA content in adipose tissue (odds ratio: 5.05, p<0.01) and erythrocytes (odds ratio: 2.2, p=0.01) is associated with an elevated risk of CHD, and the concentration of trans-linoleic acid (C18:2trans) in plasma phospholipids is correlated with an increased risk of ischemic heart disease (odds ratio: 1.68, p=0.01). However, these studies were not consistent about whether specific TFA isomers have different effects on CHD risk. Because the composition of TFA differs depending on its source (industrial vs. ruminant), it is plausible that TFAs from different sources could influence health outcomes in different ways. This is especially apparent given the beneficial properties of some ruminant TFAs (eg, conjugated linoleic acid).14,15 However, few studies have addressed this issue, and the limited data about the role of different sources of TFAs in risk for CHD is contradictory. Clearly, the relationship between different sources of TFAs and disease risk should be a focus of future research.
♦ Type 2 Diabetes
Given the connection between TFA consumption and risk for CHD and the high correlation between CHD and type 2 diabetes,16 it seems plausible that TFAs might also influence the development of diabetes and other metabolic disorders. One prospective study of 84,941 females with 16 years of follow-up reported that after adjustment for other risk factors, TFA intake was positively associated with the incidence of type 2 diabetes (p<0.001, relative risk of highest quintile to lowest quintile, 95% CI: 1.23-1.56).17 A 2% increase in energy from TFAs in middle-aged women was associated with a 1.39 higher incidence rate of type 2 diabetes.18 These findings were further supported by the observation that trans-linoleic acid consumption increases insulin resistance in overweight men and women.19 Recent primate studies show that when African green monkeys were fed a diet high in TFAs (8% of energy) for 6 years, they had increased abdominal fat and reduced insulin sensitivity.20
♦ Cancer
Several studies have explored the relationship between the incidence of cancer and consumption of different types of fatty acids. In general, they found that cancer incidence is more closely related to total fat consumption or energy intake than the type of fat consumed. However, very recent studies report that increasing levels of serum phospholipid TFAs are associated with an increased risk of breast cancer and early-stage prostate cancer.21-23 Moreover, increased consumption of TFAs increases the risk of colon cancer by two-fold in postmenopausal women.24 Several studies have also shown correlations between consumption of vegetable oils and cancer mortality, which might be explained by the TFA composition of these oils.25-27 Although only a few studies have examined the relationship between TFAs and cancer, they have shown a positive association.
How TFAs Work
Fatty acids are potent bioactive components that regulate cellular function through a wide range of physiological processes.28-31 Because fatty acids are components of phospholipids, they modulate membrane fluidity and the responses of membrane receptors and signaling pathways. Fatty acids and their acyl-CoA metabolites also directly or indirectly modulate metabolic and inflammatory responses through their regulation of gene expression, allosteric inhibition of enzymes, or modulation of ion channels.29
However, despite the abundance of epidemiological reports linking the intake of TFAs with disease risk, only a few studies have addressed the mechanisms of how TFAs are involved in disease etiology. Specifically, they have looked at how TFAs affect serum cholesterol and inflammation.
♦ Blood Lipids
Evidence from several controlled human intervention studies indicates that consumption of TFAs increases total and low-density lipoprotein (LDL) cholesterol and triglycerides in the same way that consumption of saturated fatty acids does. The studies also showed that consumption of TFAs decreases high-density lipoprotein (HDL) cholesterol, compared with consumption of cis-monounsaturated or cis-polyunsaturated fatty acids.32,33 A meta analysis of 60 controlled trials on the relationship between dietary fat consumption and plasma lipids reported that replacing TFAs with either carbohydrates or cis unsaturated fatty acids had the largest effects on lowering the ratio of total cholesterol to HDL cholesterol.33 Additional studies have associated TFA consumption with increased LDL particle size, which is also a risk factor for CHD.34,35
A human intervention study by Matthan et al. attempted to explain the changes in blood lipids by measuring kinetic parameters of cholesterol metabolism.36 Both saturated fat and partially hydrogenated fat, which are rich in TFAs, increase LDL cholesterol concentrations because the body removes them from the blood less efficiently. Partially hydrogenated fat also results in lower HDL cholesterol concentrations by increasing its clearance from the blood. In a clinical trial comparing people who consumed diets rich in polyunsaturated or saturated fatty acids, men who consumed diets high in TFAs had increased activity in their plasma of cholesteryl ester transfer protein, the main enzyme responsible for the transfer of cholesterol ester from HDL to LDL or very-low-density lipoprotein (VLDL).37 TFAs also increase hepatic VLDL secretion and decrease VLDL particle size in cultured human hepatoma cell lines.38 Finally, TFAs can cause alterations in adipose function such as decreased adipocyte differentiation and enhanced lipolysis, both of which may contribute to ectopic fat deposition and insulin resistance.31,39,40 Thus, it appears that TFAs mediate blood lipids by altering their metabolism in the blood and through their effects on liver and adipose tissue, which are involved in lipid anabolism and catabolism. Taken as a whole, alterations in serum lipids are likely an important factor through which dietary TFAs increase disease risk.
♦ Inflammation
Blood lipids may not be the only mechanism through which TFAs affect the body. In recent years, inflammation has come to the forefront as a major contributor to the development of numerous metabolic diseases. Thus, it is not surprising that TFAs appear to induce inflammation, which likely contributes to the increased risk of
disease. Studies show that increased TFA consumption, as measured by dietary intake or plasma membrane fatty acid composition, increases circulating concentrations of inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, C-reactive protein, and monocyte chemoattractant protein-1.41-43 Randomized controlled trials involving patients with hypercholesterolemia showed greater production of inflammatory cytokines in cultures of mononuclear cells taken from participants who were fed a diet high in TFAs over the course of 1 month, compared with cells taken from members of a control group.44 In addition, feeding TFAs to rats was found to alter gene expression profiles in adipose tissue, increasing inflammatory adipokines and decreasing anti-inflammatory adipokines.45
Taken together, it appears that both immune cells and adipose tissue contribute to the increase in circulating inflammatory mediators. Chronically elevated levels of inflammatory mediators are known to modulate cellular function and signaling; this results in the initiation and progression of atherosclerosis and insulin resistance.8,46 In support, several studies have shown that TFAs cause endothelial dysfunction. For example, intake of TFAs is positively associated with levels of soluble cell adhesion molecules and reduced brachial artery flow.32,42,47 Therefore, impaired endothelial cell function, increased inflammation, and altered plasma lipids are likely the major mechanisms through which TFAs enhance the risk of metabolic diseases.
Conclusion
Consumption of TFAs is now recognized as a potent health risk and, thus, legislation that limits or bans their use in the processing and preparation of food seems warranted. Replacing dietary TFAs with cis-unsaturated fatty acids, rather than saturated fatty acids, would be the best scenario to promote optimal health. Although the exact molecular mechanisms explaining the detrimental effects of TFAs have not been elucidated, it appears that TFA-induced changes in blood lipids and increased inflammation play key roles in risk of CHD and other chronic diseases. It is likely that future research will clarify the bioactive functions of individual TFA species, which also will shed light on differences between TFAs derived from natural sources (animal fat) and industrial sources. Regardless, it is advisable to limit TFA intake in order to minimize the adverse health effects that are associated with their consumption. MM
So Young Bu is a postdoctoral research fellow and Douglas Mashek is an assistant professor in the department of food science and nutrition at the University of Minnesota.
References
1. Food and Drug Administration, HHS. Food labeling: Trans fatty acids in nutrition labeling, nutrient content claims, and health claims. Final rule. Fed Regist. 2003;68(133):41433-506.
2. Emken EA. Nutrition and biochemistry of trans and positional fatty acid isomers in hydrogenated oils. Annu Rev Nutr. 1984;4:339-76.
3. Eckel RH, Borra S, Lichtenstein AH, Yin-Piazza SY, Trans Fat Conference Planning Group. Understanding the complexity of trans fatty acid reduction in the American diet: American Heart Association Trans Fat Conference 2006: Report of the Trans Fat Conference Planning Group. Circulation. 2007;115(16):2231-46.
4. Stender S, Dyerberg J, Bysted A, Leth T, Astrup A. A trans world journey. Atheroscler Suppl. 2006;7(2):
47-52.
5. Stender S, Dyerberg J, Astrup A. High levels of industrially produced trans fat in popular fast foods. N Engl J Med. 2006;354(15):1650-2.
6. Wagner K, Plasser E, Proell C, Kanzler S. Com-prehensive studies on the trans fatty acid content of Austrian foods: Convenience products, fast food and fats. Food Chemistry. 2008;108:1054-60.
7. Harnack L, Lee S, Schakel SF, Duval S, Luepker RV, Arnett DK. Trends in the trans-fatty acid composition of the diet in a metropolitan area: The Minnesota Heart Survey. J Am Diet Assoc. 2003;103(9):1160-6.
8. Oomen CM, Ocké MC, Feskens EJ, van Erp-Baart MJ, Kok FJ, Kromhout D. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: A prospective population-based study. Lancet. 2001;357(9258):746-51.
9. Oh K, Hu FB, Manson JE, Stampfer MJ, Willett WC. Dietary fat intake and risk of coronary heart disease in women: 20 years of follow-up of the Nurses’ Health Study. Am J Epidemiol. 2005;161(7):672-9.
10. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006;354(15):1601-3.
11. Baylin A, Kabagambe EK, Ascherio A, Spiegelman D, Campos H. High 18:2 trans-fatty acids in adipose tissue are associated with increased risk of nonfatal acute myocardial infarction in Costa Rican adults. J Nutr. 2003;133(4):1186-91.
12. Sun Q, Ma J, Campos H, et al. A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease. Circulation. 2007;115(14):1858-65.
13. Lemaitre RN, King IB, Mozaffarian D, et al. Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study. Circulation. 2006;114(3):209-15.
14. Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G. Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem. 2006;17(12):789-810.
15. Chardigny J, Destaillats F, Malpuech-Brugere C, et al. Do trans fatty acids from industrially produced sources and from natural sources have the same effect on cardiovascular disease risk factors in healthy subjects? Results of the Trans Fatty Acids Collaboration (TRANSFACT) study. Am J Clin Nutr. 2008;87(3):
558-66.
16. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035-8.
17. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345(11):790-7.
18. Salmeron J, Hu FB, Manson JE, et al. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr. 2001;73:1019-1026.
19. Lefevre M, Lovejoy JC, Smith SR, et al. Comparison of the acute response to meals enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes. Metabolism. 2005;54(12):1652-8.
20. Kavanagh K, Jones KL, Sawyer J, et al. Trans fat diet induces abdominal obesity and changes in insulin sensitivity in monkeys. Obesity. 2007;15:1675-84.
21. Kim EH, Willett WC, Colditz GA, et al. Dietary fat and risk of postmenopausal breast cancer in a 20-year follow-up. Am J Epidemiol. 2006;164(10):990-7.
22. Chajes V, Thiebaut AC, Rotival M, et al. Association between serum trans-monounsaturated fatty acids and breast cancer risk in the E3N-EPIC study. Am J Epidemiol. 2008;167(11):1312-20.
23. Chavarro JE, Stampfer MJ, Campos H, Kurth T, Willett WC, Ma J. A prospective study of trans-fatty acid levels in blood and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(1):95-101.
24. Slattery ML, Benson J, Ma KN, Schaffer D, Potter JD. Trans-fatty acids and colon cancer. Nutr Cancer. 2001;39(2):170-5.
25. Neuhouser ML, Barnett MJ, Kristal AR, et al. (n-6) PUFA increase and dairy foods decrease prostate cancer risk in heavy smokers. J Nutr. 2007;137(7):1821-7.
26. Slattery ML, Potter JD, Duncan DM, Berry TD. Dietary fats and colon cancer: Assessment of risk associated with specific fatty acids. Int J Cancer. 1997;73(5):670-7.
27. Velie E, Kulldorff M, Schairer C, Block G, Albanes D, Schatzkin A. Dietary fat, fat subtypes, and breast cancer in postmenopausal women: A prospective cohort study. J Natl Cancer Inst. 2000;92(10):833-9.
28. Barnard DE, Sampugna J, Berlin E, Bhathena SJ, Knapka JJ. Dietary trans fatty acids modulate erythrocyte membrane fatty acyl composition and insulin binding in monkeys. J Nutr Biochem. 1990;1(4):190-5.
29. Mashek DG, Li LO, Coleman RA. Long-chain acyl-CoA synthetases and fatty acid channeling. Future Lipidology. 2007;2(4):465-76.
30. Natarajan S, Ibrahim A, Ghafoorunissa. Dietary trans fatty acids alter diaphragm phospholipid fatty acid composition, triacylglycerol content and glucose transport in rats. Br J Nutr. 2005;93(6):829-33.
31. Ibrahim A, Natrajan S, Ghafoorunissa R. Dietary trans-fatty acids alter adipocyte plasma membrane fatty acid composition and insulin sensitivity in rats. Metabolism. 2005;54(2):240-6.
32. de Roos NM, Bots ML, Katan MB. Replacement of dietary saturated fatty acids by trans fatty acids lowers serum HDL cholesterol and impairs endothelial function in healthy men and women. Arterioscler Thromb Vasc Biol. 2001;21(7):1233-7.
33. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: A meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77(5):1146-55.
34. Ascherio A, Katan MB, Zock PL, Stampfer MJ, Willett WC. Trans fatty acids and coronary heart disease. N Engl J Med. 1999;340(25):1994-8.
35. Mauger JF, Lichtenstein AH, Ausman LM, et al. Effect of different forms of dietary hydrogenated fats on LDL particle size. Am J Clin Nutr. 2003;78(3):
370-5.
36. Matthan NR, Welty FK, Barrett PH, et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol. 2004;24(6):1092-7.
37. van Tol A, Zock PL, van Gent T, Scheek LM, Katan MB. Dietary trans fatty acids increase serum cholesterylester transfer protein activity in man. Atherosclerosis. 1995;115(1):129-34.
38. Dashti N, Feng Q, Freeman MR, Gandhi M, Franklin FA. Trans polyunsaturated fatty acids have more adverse effects than saturated fatty acids on the concentration and composition of lipoproteins secreted by human hepatoma HepG2 cells. J Nutr. 2002;132(9):2651-9.
39. Panigrahi K, Sampugna J. Effects of trans fatty acids on lipid accumulation in 3T3-L1 cells. Lipids. 1993;28(12):1069-74.
40. Xu J, Nakamura MT, Cho HP, Clarke SD. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem. 1999;274(133):23577-83.
41. Mozaffarian D, Pischon T, Hankinson SE, et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004;79(4):
606-12.
42. Baer DJ, Judd JT, Clevidence BA, Tracy RP. Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: A randomized crossover study. Am J Clin Nutr. 2004;79(6):969-73.
43. Mozaffarian D, Rimm EB, King IB, Lawler RL, McDonald GB, Levy WC. Trans fatty acids and systemic inflammation in heart failure. Am J Clin Nutr. 2004;80(6):1521-5.
44. Han SN, Leka LS, Lichtenstein AH, Ausman LM, Schaefer EJ, Meydani SN. Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory responses of adults with moderate hypercholesterolemia. J Lipid Res. 2002;43(3):445-52.
45. Saravanan N, Haseeb A, Ehtesham NZ, Ghafoorunissa. Differential effects of dietary saturated and trans-fatty acids on expression of genes associated with insulin sensitivity in rat adipose tissue. Eur J Endocrinol. 2005;153(1):159-65.
46. Hotamisligil GS. Role of endoplasmic reticulum stress and c-jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes. 2005;54 Suppl 2:S73-8.
47. Lopez-Garcia E, Schulze MB, Meigs JB, et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005;135(3):562-6.