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REVIEW Proceedings from the 2013 Canadian Nutrition Society Conference on Advances in Dietary Fats and Nutrition Bruce Holub, David M. Mutch, Grant N. Pierce, Delfin Rodriguez-Leyva, Michel Aliani, Sheila Innis, William Yan, Benoit Lamarche, Patrick Couture, and David W.L. Ma

Abstract: The science of lipid research continues to rapidly evolve and change. New knowledge enhances our understanding and perspectives on the role of lipids in health and nutrition. However, new knowledge also challenges currently held opinions. The following are the proceedings of the 2013 Canadian Nutrition Society Conference on the Advances in Dietary Fats and Nutrition. Content experts presented state-of-the-art information regarding our understanding of fish oil and plant-based n-3 polyunsaturated fatty acids, nutrigenomics, pediatrics, regulatory affairs, and trans fats. These important contributions aim to provide clarity on the latest advances and opinions regarding the role of different types of fats in health. Key words: alpha-linolenic acid, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid, omega-3, saturated fat, trans fat, flaxseed, cardiovascular disease, coronary heart disease, central nervous system, fatty acid desaturases, single nucleotide polymorphisms, health claim. Résumé : La recherche sur les lipides évolue rapidement et tout en se modifiant. Les nouvelles connaissances améliorent notre compréhension et les perspectives sur le rôle des lipides dans la santé et l'alimentation. Toutefois, les nouvelles connaissances mettent en doute les opinions répandues a` ce jour. Voici le compte-rendu du Congrès 2013 de la Société canadienne de nutrition sur les développements au sujet des gras alimentaires et de la nutrition. Des experts en la matière présentent les dernières observations concernant l'huile de poisson et les acides gras polyinsaturés n-3 a` base de plante, la nutrigénomique, la pédiatrie, la régulation et les gras trans. Ces importantes contributions ont pour objectif de présenter les dernières observations et opinions au sujet du rôle de divers types de gras sur la santé. [Traduit par la Rédaction] Mots-clés : acide alpha-linolénique, acide linoléique, acide eicosapentaénoïque, acide docosahexanoïque, acide arachidonique, oméga-3, gras saturés, gras trans, graine de lin, maladie cardiovasculaire, coronaropathie, système nerveux central, désaturases des acides gras, polymorphismes singuliers de nucléotides, allégations sanitaires.

Dr. Bruce Holub. An update regarding the effects of DHA–EPA omega-3 in optimizing health and the prevention–management of chronic disease The importance of docosahexaenoic acid (DHA, 22:6 n-3), an omega-3 fatty acid, as a physiologically essential fatty acid in the brain and retina to support optimal cognitive functioning and visual acuity, respectively, is becoming more apparent (www. dhaomega3.org). In view of the very limited bioconversion of alpha-linolenic acid (ALA, 18:3 n-3) to DHA, averaging 3.5% in adults, recent clinical trials have focused on the potential benefits of supplementation with preformed DHA. It is noted that the desaturation product of ALA is stearidonic acid (18:4 n-3), and it is now found in some genetically modified seeds and oils and gives a 3–4-fold greater rise in blood levels of eicosapentaenoic acid (EPA, 20:5 n-3) when compared with ALA (James et al. 2003) after a few weeks of daily feeding (without any increase in circulating DHA). Makrides et al. (2010) observed a significantly lower prevalence of preterm babies, low birth weight infants, and admission of new-

borns to intensive care by 52%, 36%, and 45%, respectively, when the pregnant mothers were supplemented with 800 mg of DHA (plus 100 mg of EPA) daily over 21 weeks of gestation compared with the placebo group. A subsequent clinical trial by Carlson et al. (2013) found that DHA supplementation (600 mg·day–1) in the last half of gestation resulted in an overall greater gestation duration and infant size. As reviewed, controlled infant feeding trials have found better visual and cognitive outcomes in some, but not all, studies with DHA levels at approximately 0.33% of the fat content (Hoffman et al. 2009). Daily intakes of DHA (from fish, enriched foods, and supplements) of 200–250 mg·day–1 would most likely provide such levels of DHA in breast milk. Recently, Richardson et al. (2012) reported a highly significant improvement in reading ability scores when schoolchildren (ages 7–9 years), who were initially in the lower 10th or 20th percentiles with respect to reading ability, received daily DHA supplementation (600 mg·day–1) over 16 weeks relative to the placebo group. Numerous systematic reviews and meta-analyses based on randomized clinical trials as reported in peer-reviewed medical

Received 10 September 2013. Accepted 6 January 2014. B. Holub, D.M. Mutch, and D.W.L. Ma. Department of Human Health and Nutritional Sciences, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada. G.N. Pierce. Canadian Centre for Agri-food Research in Health and Medicine, St Boniface Hospital Research Centre, Department of Physiology, Faculties of Medicine and Pharmacy, University of Manitoba, Winnipeg, MB, Canada. D. Rodriguez-Leyva. V.I. Lenin University Hospital, Cardiovascular Research Division, s/n Lenin Avenue, Holguin 80100, Cuba. M. Aliani. Department of Human Nutritional Sciences, Faculty of Human Ecology, University of Manitoba, Winnipeg, MB, Canada. S. Innis. Department of Paediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada. W. Yan. Bureau of Nutritional Sciences, Food Directorate, Health Canada, Ottawa, ON K1A 0K9, Canada. B. Lamarche and P. Couture. Institute of Nutraceuticals and Functional Foods, Laval University, Québec, QC G1V 0A6, Canada. Corresponding author: David W.L. Ma (e-mail: [email protected]). Appl. Physiol. Nutr. Metab. 39: 754–762 (2014) dx.doi.org/10.1139/apnm-2013-0418

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journals have been published during the past decade on DHA– EPA omega-3 fatty intakes (via diet and supplementation) and cardiovascular-related outcomes. The majority of these have concluded with benefits of such enhanced omega-3 intakes using such end-points. A recent review and meta-analysis (Rizos et al. 2012) concluded that omega-3 supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on the eligible clinical trials that they selected for inclusion. Included amongst the various shortcomings in most of the trials, as reviewed, was the failure to measure compliance based on DHA–EPA measures in circulating biomarkers as incomplete compliance is a frequent problem over extended time periods. Despite the various shortcomings, this recent review by Rizos et al. (2012) reported the overall risk for cardiac death, sudden death, and myocardial infarction to have relative risks that were lower in the omega-3 supplemented groups (relative to placebo controls) by 9%, 13%, and 11%, respectively (although not reaching statistical significance, based on a very rigorous criteria for such). An elevated triglyceride level is a very significant risk factor for cardiovascular disease and associated mortality. Even moderately elevated levels of circulating triglyceride (150–199 mg/100 mL or 1.7–2.2 mmol·L–1), which are highly prevalent in the population and includes many people on statin treatment to lower cholesterol, carry a significantly increased risk for heart disease and are considered “borderline-high” in the recent scientific statement from the American Heart Association on triglycerides and cardiovascular disease (Miller et al. 2011). In fact, that review indicates, by the age of 40 years, almost half of US males and a considerable portion of females do not have triglyceride levels designated as “desirable” (below 150 mg/100 mL). As reviewed on www.dhaomega3. org, the degree of triglyceride lowering typically amounts to approximately 7%–10% per 1000 mg of EPA plus DHA daily such that 2000 mg or 3000 mg can be expected to lower blood triglycerides by approximately 14%–20% and 21%–35%, respectively. Such triglyceride lowering is usually attained within 3–4 weeks and can be maintained for years pending ongoing supplementation. Brasky et al. (2013) recently reported a significant positive relationship between higher blood levels of DHA and prostate cancer risk, but no statistically significant trend was found in the case of EPA, and they concluded that recommendations to increase omega-3 polyunsaturated fatty acids (PUFA) intake should consider its potential risks. It is noteworthy that Brasky et al. (2013) did not evaluate the intake of long-chain omega-3 fatty acids to the risk of prostate cancer. It is also of interest to note that Brasky et al. (2013) did not include reference to the publication by Torfadottir et al. (2013) who reported upon finding no association between overall fish consumption in early or midlife and prostate cancer risk. However, there was some evidence that “salted” or “smoked” fish may increase the risk of advanced prostate cancer. Interestingly, men consuming fish oil in later life had a lower risk of advanced prostate cancer and no association was found for early life or midlife consumption. Torfadottir et al. (2013) concluded that fish oil consumption may be protective against the progression of prostate cancer in elderly men. On the topic of DHA–EPA supplementation in health care and clinical applications, a major study led by Dr. Charmaine Lok on kidney patients across North America who were receiving dialysis found that the time to loss of graft patency, time to thrombosis, and time to cardiovascular events were all significantly improved in the group supplemented with 2400 mg EPA plus DHA daily over 12 months compared with the placebo group (Lok et al. 2012). Very recently, Daak et al. (2013) reported upon marked reductions in the rates of clinical vaso-occlusive crises and sickle cell complications in a randomized, placebo-controlled, double-blind trial when pediatric patients (average age of 8 years) were given encapsulated DHA–EPA daily (25 mg·kg−1 body weight) for 1 year. Other areas of very active research recently includes the potential benefits

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of higher intakes of DHA–EPA to alleviate the severity of traumatic brain injury and associated inflammation (Michael-Titus and Priestley 2014) and to reduce the occurrence and severity of agerelated ocular disorders such as dry eye syndrome (Kangari et al. 2013). It is noted that recent reviews have indicated that an insufficient intake of DHA–EPA from fish or seafood and not the overall dietary ratio of omega-6–omega-3 fatty acids is of importance for overall health and disease prevention and management. Further information on these and other published research updates on DHA–EPA omega-3 can be obtained at www.dhaomega3. org.

Dr. David M. Mutch. Fatty acid desaturase genes: promising targets for nutrigenomics research Fatty acids are capable of regulating a myriad of molecular processes that can influence an individual's health; however, different fatty acids affect these processes in different ways. Considerable nutritional, biochemical, and epidemiological research has led to widespread conclusions that trans and saturated fatty acids (TFA and SFA, respectively) are associated with adverse effects on health, such as an increased risk for heart disease and inflammation, whereas monounsaturated and polyunsaturated fatty acids (MUFA and PUFA, respectively) have cardioprotective benefits (Willett 2012). Thus, current dietary recommendations encourage a reduction in SFA intake and an increase in MUFA and PUFA. This can be accomplished by adopting specific diets (e.g., the MUFA-enriched Mediterranean diet) or consuming nutritional supplements (e.g., omega-3 PUFA fish oils). Although these dietary recommendations stem from previously conducted cross-sectional and intervention studies, it is important to recognize that most of the past research has focused on populations rather than individuals. Dietary recommendations produced from population-based research holds a practical merit; however, evidence now illustrates that individuals can experience substantially different responses to the same intervention. For example, significant inter-individual differences in LDL-cholesterol and circulating eicosanoid levels have been observed following omega-3 supplementation (Lovegrove and Gitau 2008; Zulyniak et al. 2013). The field of nutrigenomics aims to unravel these inter-individual differences by considering diet– gene interactions, which can subsequently lead to improvements in our ability to predict a person's response to an intervention and prevent the development of disease (Mutch et al. 2005). Although levels of blood fatty acids are influenced by an individual's dietary habits, evidence demonstrates that circulating fatty acid levels are also regulated by an underlying genetic component. Several genome-wide association studies have been conducted in recent years to explore the contribution of common genetic variants to blood PUFA levels. In 2009, Tanaka et al. studied over 1000 subjects from the InCHIANTI study and reported that single nucleotide polymorphisms (SNPs) located in the fatty acid desaturase (FADS) gene cluster, comprised of three fatty acid desaturase genes (FADS1, FADS2, and FADS3), were highly associated with plasma levels of omega-3 and omega-6 PUFA (Tanaka et al. 2009). Although the function of FADS3 remains unclear, FADS1 and FADS2 code for ⌬-5 and ⌬-6 desaturase enzymes, respectively (Merino et al. 2010). These enzymes play a key role in the conversion of essential fatty acids (linoleic acid (LA), ALA) into their long-chain counter parts (arachidonic acid (AA), EPA). The results of the aforementioned genome-wide association studies indicated that individuals carrying the minor allele for a SNP in the FADS gene cluster had lower levels of circulating AA and EPA. Thus the findings of Tanaka et al. (2009) provided strong evidence that variation in the FADS gene cluster had a significant impact on plasma PUFA levels. Numerous targeted studies have also been performed showing that SNPs in the FADS gene cluster are associated with alterations in PUFA levels in plasma, serum phospholipids, and erythrocyte Published by NRC Research Press

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membranes (see Merino et al. 2010 for a thorough review of the literature). Many of these SNPs have also been shown to influence fatty acid composition in adipose tissue (Baylin et al. 2007) and breast milk (Xie and Innis 2008), and they have been associated with the incidence of chronic diseases such as cardiovascular disease (Martinelli et al. 2008) and metabolic syndrome (Sergeant et al. 2012). Furthermore, emerging evidence postulates that variation in the FADS gene cluster may contribute to health disparities between different ethnicities (Sergeant et al. 2012; Merino et al. 2010). In all of the aforementioned research, minor allele carriers were found to have reduced levels of AA and EPA. This suggests that minor allele carriers of FADS variants may have reduced FADS1 and (or) FADS2 enzyme activity, and therefore a reduced capacity to convert essential fatty acids into long chain omega-3 and omega-6 fatty acids. It is noteworthy that most of the research in the field has not measured FADS1 or FADS2 enzyme activity directly, but has rather estimated activity using fatty acid ratios. For example, FADS1 and FADS2 activities are commonly estimated using the product-toprecursor ratios of AA/DGLA (dihomo-␥-linolenic acid) and GLA (␥-linolenic acid)/LA, respectively. This has garnered some criticism because circulating fatty acids levels reflect both dietary intake and endogenous metabolism; something that is indistinguishable using the product-to-precursor ratio approach. However, a recent study by Gillingham et al. (2013) examined ALA metabolism using a 13C stable isotope and found that results were comparable with estimates made using the product-to-precursor ratio method. The crucial role of FADS1 and FADS2 in the metabolism of essential fatty acids, coupled with the knowledge that variation in the FADS gene cluster can influence desaturase activity, positions these genes as attractive candidates for nutrigenomics research. Therefore, it is now possible to classify individuals as either “high” or “low” converters based on SNPs in the FADS gene cluster. To date, there are only a few instances in the literature in which this method of classification has been utilized; however, these examples provide exciting additions to the nutrigenomics community. For example, Gillingham et al. (2013) recently reported that minor allele carriers of a SNP located in FADS1 produced more EPA following the 4-week consumption of a flaxseedenriched diet compared with either a Western diet or a high-oleic acid canola oil diet. Most importantly, the levels of EPA produced in minor allele carriers who consumed the flaxseed-enriched diet were comparable with carriers of the common allele who consumed a standard Western diet. It is therefore tempting to speculate that providing “low converters” with an ALA-enriched diet may compensate for a genetic predisposition for reduced FADS activity. Conversely, the potential for feedback regulation of the FADS pathway by EPA + DHA has been reported. This is relevant as it could lead to significant changes in blood and tissue fatty acid profiles that ultimately influence an individual's risk for chronic disease. For example, a reduction in hepatic FADS1 and FADS2 activities was observed in mice consuming diets supplemented with EPA + DHA (Cho et al. 1999). Similarly, DHA synthesis was inhibited in humans consuming a fish-based diet, suggesting reduced FADS2 activity (Pawlosky et al. 2003). Only a few studies have considered if EPA + DHA intake can regulate FADS activity in a genotype-specific manner. Al-Hilal et al. (2013) recently reported an interaction between EPA + DHA intake and FADS1 activity in individuals carrying the minor allele of a SNP located near the FADS1 gene. In a second study, Cormier et al. (2012) examined whether SNPs in the FADS gene cluster could influence triglyceride levels following omega-3 supplementation. Although Cormier et al. (2012) found that all subjects experienced the expected reduction in plasma triglycerides, they did not find evidence that the reduction differed according to FADS genotype. Together, these nutrigenomic studies highlight emerging research reflect-

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ing the current interest to investigate whether “high” and “low” converters elicit distinct responses to dietary omega-3s. Although the previously discussed nutrigenomic studies were conducted in relatively small populations, they represent promising additions to the field. The search for robust candidate genes is often hampered by a lack of reproducibility; however, the FADS gene cluster has emerged as a strong and suitable candidate for nutrigenomics research. Continued efforts in this promising area will further improve our understanding of how SNPs in the FADS gene cluster regulate fatty acid metabolism and contribute to health disparities between different populations. Moreover, targeting the FADS gene cluster for nutrigenomics research will help elucidate whether a genetic susceptibility for reduced FADS activity can be circumvented with personalized dietary recommendations.

Dr. Grant N. Pierce, Dr. Delfin Rodriguez-Leyva, and Dr. Michel Aliani. Plant omega-3 fatty acids: their use in the fight against cardiovascular disease The vast majority of research on the health-related benefits of n-3 PUFAs has been carried out using marine animal sources of these fatty acids. Most of this work has been done with the long chain n-3 fatty acids EPA and DHA obtained from fish (Willett 2012). However, shorter chain omega-3 fatty acids can be obtained from plant sources. The most abundant of these, and the most biologically important one, is ALA. This plant-derived PUFA is structurally similar to marine-based n-3 PUFAs in that it is an n-3 fatty acid, but it is still structurally distinct in both length and conformation (Rodriguez-Leyva et al. 2010). ALA has an 18:3 fatty acid composition, whereas EPA and DHA are longer chain 20:5 and 22:6 fatty acid moieties, respectively. Through a series of desaturation and elongation steps, ALA can be metabolized within the body to EPA and DHA (Rodriguez-Leyva et al. 2010). This is relatively inefficient and varies depending upon the species examined. Metabolism of ALA to EPA and DHA is almost nonexistent in rabbits (Dupasquier et al. 2006), modest in mice (Dupasquier et al. 2007; Bassett et al. 2011), and minimal in humans (Austria et al. 2008; Patenaude et al. 2009). In humans, the metabolism of ALA to longer chain fatty acid species may be influenced by gender (Patenaude et al. 2009). Women may be capable of a more efficient metabolism to long chain fatty acids than men can achieve; however, further work to clearly prove this remains to be done. The plant sources of ALA are varied but clear differences exist. The richest sources of ALA found in commonly ingested plants include soybeans, canola, oats, walnuts, and flaxseed (Rodriguez-Leyva et al. 2010). Flaxseed is the richest source of ALA of these 5 plants (Rodriguez-Leyva et al. 2010). The ALA can be extracted from these plants in an oil form to provide an even more concentrated extract or incorporated into salad dressings or margarines to supplement the diet. Flaxseed can also be baked into a variety of products (bagels, nutrition bars, muffins, pasta, buns, cereals, tea biscuits) (Leyva et al. 2011) without decomposition of its ALA content (Malcolmson et al. 2000). A number of epidemiological studies have identified a relationship of ALA with decreases in the incidence of cardiovascular disease and clinical events. These studies include the MRFIT Study (Dolecek 1992), the NHLBI Family Heart Study (Djousse et al. 2001), the Lyon Diet Heart Study (de Lorgeril et al. 1999), the Health Professionals Follow Up (Ascherio et al. 1996), the Nurse's Health Study (Hu et al. 1999), and others. These have involved in total over 140 000 subjects and decades of follow up. They have shown a strong protective effect of plasma and tissue ALA levels on cardiovascular disease. Although some recent research (Wang et al. 2006; Kromhout et al. 2010) has refuted the negative relationship of elevated ALA levels and cardiovascular events, enough persuasive research in favour of such a relationship has encouraged Published by NRC Research Press

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further work into the mechanism whereby ALA, and the foods that contain ALA, may provide a cardiovascular benefit. The mechanisms whereby ALA may protect the body from cardiovascular disease are varied. Atherosclerotic heart disease induced by high cholesterol or trans fat enriched diets have been prevented or depressed significantly by the inclusion of flaxseed or ALA in the diet (Dupasquier et al. 2006, 2007; Bassett et al. 2011). Flaxseed has an anti-arrhythmic action as well that has been attributed to its ALA content (Ander et al. 2004). Dietary flaxseed can also prevent atherosclerotic conditions from inhibiting vascular relaxation (Dupasquier et al. 2006). ALA may inhibit dangerous arrhythmias and vascular contractile dysfunction through an inhibition of intracellular Ca2+ transport pathways in cardiomyocytes and smooth muscle (Dupasquier et al. 2007). All of these mechanisms of action may participate together or in isolation to protect the heart from challenges that may result in cardiovascular events. Further work to identify and support the efficacy of flaxseed and its components in cardiovascular disease are warranted. In summary, epidemiological, basic science investigations in animal models of cardiovascular disease and emerging interventional clinical trials support the efficacy of ALA and foods that contain ALA as being unusually effective in the fight against heart disease and stroke. It remains to understand more about the mechanisms whereby this can be achieved, the manners in which we can incorporate ALA into the diet, the doses of ALA needed to achieve desirable clinical end-points, and the potential for nonspecific side effects at higher doses. One thing is clear: ALA and foods that are enriched in ALA deserve increased research attention as viable dietary strategies to promote healthy living.

Dr. Sheila Innis. Advances in dietary fats and nutrition – maternal and infant health Scientific advances in recent decades have made it clear that maternal diet fat quality, specifically the types of fatty acids, is a significant determinant of the fatty acids transferred across the placenta and secreted in milk (Innis 2004, 2005; Jensen 1999). This in turn can lead to profound changes in the fatty acids accumulated in fetal and infant tissues, which is not without consequence. This is overlaid on increasing understanding that different SFAs, MUFAs, and omega-6 and omega-3 PUFAs all play specific and important roles in the regulation of metabolic pathways, gene expression, and cell communication (Innis 2011). This is the result of both direct effects of the fatty acid itself and fatty acid or fatty acid metabolites that function as signal molecules (Kim and Spector 2013a; Jump 2008). At the same time, the last century has seen substantial shifts in dietary fat intakes, driven in part by concerns that certain fatty acids may contribute to increased risk of cardiovascular or other diseases. However, these shifts in dietary fat preceded knowledge of the important roles of n-3 fatty acids, the roles of fatty acids in regulation of gene expression, eicosanoid biology, and acylated signal molecules and other mediators (Jump 2008; Kim and Spector 2013b; Rangel-Huerta et al. 2012). The simplistic understanding of the roles of dietary fat and membrane biology and the misplaced belief that the brain is protected during poor nutrition through much of the first part of 19th century perhaps also contributed to the lack of the importance of diet fat quality in pregnancy and lactation to support the complex processes involved in human development. Key points for consideration are: (i) persuasive evidence that placental transfer and secretion of unsaturated fatty acids in human milk is variable and readily influenced by maternal diet; (ii) maternal dietary fat quality impacts fetal and infant tissue fatty acid accretion, including that in the developing brain, liver, intestine, adipose, and other organs; (iii) much of diet fat, either by direct consumption or indirectly through livestock feeds, has changed in last century; and (iv) a growing body of evidence sug-

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gests that omega-3 fatty acid insufficiency occurs in pregnancy, lactation, and young children and contributes to the failure to reach neurological potential and increases the risk of several diseases. Observation- and intervention-based studies have shown that placental transfer and secretion into breast milk of unsaturated fatty acids including TFA, LA, ALA, and DHA increases with increasing amounts of the respective fatty acid in the mother's diet. DHA is required by the developing central nervous system, but it is replaced by omega-6 PUFA, including docosatetraenoic acid and docosapentaenoic acid, when the maternal diet is low in omega-3 or has high levels of LA (Innis 2011; Novak et al. 2008). However, although omega-6 docosatetraenoic acid and omega-6 docosapentaenoic acid are acylated into membrane lipids they do not fulfill the roles of DHA in neural development or brain and retina function. Higher dietary intakes of preformed DHA, for example in fish, reduce the risk of DHA inadequacy, as this obviates the needs for endogenous synthesis from ALA and overcomes any competition by omega-6 PUFA. Dietary intakes of LA have increased worldwide, but this has not been matched by increases in omega-3 PUFA, giving high and unbalanced dietary PUFA intakes (Innis 2011; Friesen and Innis 2010). Intervention studies to show that supplemental DHA in pregnancy, lactation, and in young children improves child neurodevelopment, and visual system test scores provide evidence that functional omega-3 fatty acid deficiency may occur among some women and children consuming usual modern human diets (Innis and Friesen 2008; Helland et al. 2003; Jensen and Lapillonne 2009; Jensen et al. 2005).

Dr. David Ma. Canadian unsaturated fat health claim This short review highlights the development of one of the newest health claims pertaining to the consumption of dietary fat and its relationship to coronary heart disease (CHD). Canada allows the use of health claims, which is a class of claims that pertains to a food's ability to reduce the risk of developing a specific disease. Disease reduction health claims require the highest degree of evidence to be permitted in the market place; a reflection of the limited number of health claims in Canada. These health claims are permitted after rigorous evaluation, because they imply that the consumption or avoidance of a food or a specific ingredient is associated with a health benefit or disease reduction. (Health Canada 2007, 2012a, 2012b). The original set of health claims was first introduced in 2000, which included a claim on the relationship between the consumption of saturated and trans fatty acids on plasma cholesterol levels and the risk of developing CHD (Health Canada 2012a). As of 2012, Health Canada approved a complementary health claim that addresses the relationship between unsaturated fat, cholesterol, and heart disease (Health Canada and The Bureau of Nutritional Sciences 2012). The scientific evidence in support of this new claim examined the effect of replacing saturated fat with unsaturated fat on blood cholesterol, which is linked to coronary heart disease. Cardiovascular disease is a leading cause of death in Canada accounting for 29% of all deaths in 2008 (Statistics Canada 2008, Public Health Agency of Canada 2009). The health and economic burden is substantial. It is estimated that approximately 1.6 million Canadians are living with heart disease or stroke. CHD and stroke contributes significantly to cardiovascular disease related death as 9 in 10 Canadians have at least one risk factor (Public Health Agency of Canada 2009, 2011). Cholesterol has been extensively studied as an important risk factor of heart disease. High blood cholesterol is associated with increased CHD risk. As early as the 1960s, large cohort studies have consistently shown a positive relationship between increasing blood cholesterol and coronary heart disease (Martin et al. 1986; Kannel et al. 1961). The prevailing evidence indicates that Published by NRC Research Press

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saturated and trans fats increase blood cholesterol. In particular, saturated fat raises low density lipoprotein cholesterol, which is a major risk factor for heart disease (Willett 2012). This is reflected in the wording of the claim stating that “… diets low in saturated and trans fats may or might reduce the risk of heart disease …” (Health Canada 2012a). The messaging in this claim provides guidance on the types of fats to limit, which stems from the scientific review demonstrating a strong linkage between saturated fat and trans fats in raising low-density lipoprotein cholesterol (LDL-c), a major heart disease risk factor (Health Canada 2012a). The development of the 2012 unsaturated fat health claim involved an extensive literature review. The basis of the unsaturated fat health claim builds upon the authoritative statement by the Food and Nutrition Board of the Institute of Medicine (2002): “Monounsaturated and polyunsaturated fatty acids reduce blood cholesterol concentrations and help lower the risk of heart disease when they replace saturated fatty acids in the diet”. There are two important elements of the 2000 and 2012 health claims to note. The initial claim recommends what to avoid, a negative health message. In contrast, the new claim provides guidance on the types of fats to select in the diet, a positive health message. It is also important to recognize that the claim recognizes the benefits of unsaturated fats, which are comprised of both MUFA and PUFA. The rationale for this guidance is based on the fact that these healthy fats are consumed together in the diet and not individually in isolation. Although there is basic research indicating differential effects of individual types of fatty acids, the literature review for the health claim reflects the practical and physiologically relevant consumption of a mixture of fatty acids. MUFA are commonly known as omega-9 fatty acids, which is mainly oleic acid in the diet, whereas PUFA include fatty acids from the omega-6 and omega-3 families of fatty acids. These healthy unsaturated fats are found in vegetable oils including canola, soy, and olive and in foods such as avocados, nuts, and nonhydrogenated margarines. The literature review included the initial screening of over 600 articles from the years 2000–2008. The year 2000 was chosen as the starting point reflecting the timing of the Institute of Medicine report. Studies reviewed were human studies assessing the effect of replacing saturated fat by MUFA or PUFA on blood cholesterol (total, LDL-c and HDL-c). The duration of the study had to be at least 2 weeks with either healthy or hyperlipidemic participants. The quality of these studies was also assessed such as the use of appropriate controls and randomization. In total, 13 highquality studies were identified and included as part of the submission to Health Canada in support of the health claim (Hodson et al. 2001; Stewart et al. 2001; Montoya et al. 2002; Rivellese et al. 2003; Muller et al. 2003; Smith et al. 2003; Gill et al. 2003; Chung et al. 2004; Thijssen and Mensink 2005; lman-Farinelli et al. 2005; Binkoski et al. 2005; Lichtenstein et al. 2006; Berglund et al. 2007). Within these 13 studies, cholesterol reduction was observed in both normal and hyperlipidemic subjects, demonstrating broad beneficial effects that are generalizable to the majority of Canadians. In terms of efficacy, the effect of replacing saturated fat with unsaturated fat in the diet on LDL-c is similar to moderate statin treatment (Hjelstuen et al. 2007). In summary, 10 of the 13 studies reported decreases in total cholesterol, whereas 11 of the 13 studies reported decreases in LDL-c by as much as 20% and HDL-c was relatively unchanged in 7 of the 12 studies. These effects on blood cholesterol levels were observable between 2 and 4 weeks. Importantly, no studies reported that unsaturated fats increased total cholesterol or LDL-c. In addition to the concentration of LDL-c, the size of these particles also influences heart health with smaller particles having a greater negative impact. The 13 studies submitted to Health Canada did not focus on particle size but it has been reported that ALA does not have a strong influence on lipoprotein particle size (Harper et al. 2006). However, there is evidence that fish oils and MUFA beneficially increase LDL-c particle size

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(Suzukawa et al. 1995; Moreno et al. 2004). Thus, these healthier fats may further reduce heart disease risk through modulation of lipoprotein particle size. In considering the value of the new unsaturated fat health claim, three important questions need to be considered. What is the net benefit? What dose is required? Is it feasible? In terms of a net benefit, based on several estimates, a 1% (of caloric energy) replacement of saturated fat by unsaturated fat would result in a 1.6%–2% decrease in coronary heart disease death and events (Jakobsen et al. 2009; Katan 2009; Mozaffarian et al. 2010). In terms of dosage and safety, some guidance comes from the American Heart Association recommending the consumption of 5%–10% of energy from omega-6 fatty acids to reduce CHD risk, which is the same recommendation set out by the Institute of Medicine (Harris et al. 2009). Overall, this health claim is also highly feasible. For example, the current intake of linoleic acid in Canadian men is near the current recommended levels of 5%–10% of energy. On a gram basis, the current recommendation for men is 14–17 g·day–1 and 1.6 g·day–1 for omega-6 and omega-3 fatty acids, respectively (Trumbo et al. 2002; Food and Nutrition Board of the Institute of Medicine 2002). Actual intake of these fats measured from the Canadian Community Health Survey reveals that Canadian men consumed 12.5 g·day–1 and 2.2 g·day–1 of omega-6 and omega-3 fatty acids, respectively, or approximately 5% of total caloric energy (Health Canada and The Office of Nutrition Policy and Promotion 2006). This Canadian unsaturated fat health claim is comparable in scope to claims in other countries including the United States (www.fda.gov), Europe (www.efsa.europa.eu), and Australia and New Zealand (www.foodstandards.gov.au). The similarity of claims in various countries and jurisdictions can be interpreted to reflect general agreement among authoritative bodies regarding the value of such a health claim and the strength of the scientific evidence. The development of the unsaturated fat health claim required the involvement of multiple groups. A health claim submission is a lengthy and rigorous process requiring significant expertise in areas related to nutrition and regulatory affairs. The petitioner of the health claim was Sean McPhee from the Vegetable Oils Industry of Canada. The University of Guelph conducted the scientific literature review. The Program in Food Safety, Nutrition and Regulatory Affairs at the University of Toronto and Agriculture and Agri-food Canada provided advice on the regulatory process and scientific literature. Soy 20/20 provided funding for the literature review. Health Canada reviewed the health claim submission and made the final decision regarding the approval of the health claim. In summary, the newest health claim provides Canadians with a new tool to better understand and select appropriate fats that contribute to a healthy diet.

Dr. William Yan. Cholesterol-lowering claims for food: Health Canada’s perspective Health claims on foods are voluntary and they must not be false, misleading, deceptive, or likely to create an erroneous impression. The Food Directorate in the Health Products and Food Branch of Health Canada is responsible for establishing standards of evidence for supporting food health claims. These standards of evidence help to ensure that health claims are substantiated with high levels of scientific scrutiny and rigour and that they comply with Section 5.(1) of the Food and Drugs Act. The framework for food health claims has evolved over the past 10 years from the approval of 5 disease risk reduction claims in 2002 to the acceptance of 5 therapeutic claims about cholesterol lowering since 2010. The addition of a health claim is no longer sufficient for a food product to be considered a drug or natural health product as long as the benefit is a result of the food's normal dietary use and the claimed benefit is substantiated. In Published by NRC Research Press

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addition, added substances (if any) would need to be present in amounts safe for consumption as foods and they would need to have a food purpose or be of dietary origin. As demonstrated by the 5 accepted cholesterol-lowering claims for plant sterols, unsaturated fat, psyllium, barley, and oat products, there is significant interest for health claims about cholesterol lowering. One of the reasons might be the relevance of cholesterol lowering to the health of Canadians: high cholesterol affects a large proportion, about 40% (Statistics Canada 2010) of the Canadian adult population and it is a recognized risk factor for heart disease. In addition, studies investigating the effect of foods on blood cholesterol have the advantage of being relatively short term (2–3 weeks) and methods used to measure blood cholesterol are well established, reliable, and reproducible. Although important progress has been accomplished for the management and use of health claims, challenges remain regarding their regulation as well as consumer understanding. However, these challenges are not unique to Canada, and Health Canada is working on strengthening international collaboration to share expertise on some of these issues.

Dr. Benoit Lamarche and Dr. Patrick Couture. An update on trans fatty acids and coronary heart disease Our understanding of how dietary fats modulate the risk of CHD has evolved quite significantly over the last 30 years. SFA has long been considered as the bad dietary fat, mostly due to its LDL-c raising effect (Mensink et al. 2003). However, TFA in foods have also recently attracted worldwide attention, owing to their undesirable effects on human health. TFA are fatty acids that include at least one double bond in a “trans” configuration, i.e., a structure in which the hydrogen atoms around this double bond are on opposite sides of the carbon chain as opposed to the “cis” configuration, in which the hydrogen atoms around the double bond are on the same side. Our experience with TFA is relatively short lived, having been introduced in westernized diet less than a century ago. At the turn of the 2000s, it was estimated that 80%–90% of dietary TFA in the US diet originated from partially hydrogenated vegetable oils (Mozaffarian et al. 2006). Margarines contributed nearly 20% of the total TFA intake in the North American diet with the remaining majority coming from numerous processed and fast foods such as cakes, cookies, pies, bread, and fried potatoes (Mozaffarian et al. 2006). The most recent meta-analysis of cohort studies has confirmed that a high intake of TFAs was associated with an increased risk of CHD (Bendsen et al. 2011). It has been estimated that each increase in TFA intake equivalent to 2% of daily energy elevates the risk of CHD by 25% (Mozaffarian et al. 2006). Data also indicated that on a gram for gram basis, TFA had a 10 times greater impact on elevating one's risk of CHD than SFA (Ascherio et al. 1999). The impact of TFA on cardiovascular health goes far beyond its effect on LDL-cholesterol levels. Unlike SFA, intake of TFA reduces plasma HDL-c concentration (Mensink et al. 2003; Katan 2000) as well as LDL-c particle size (Mauger et al. 2003), both of which are important risk factors for CHD (Lamarche et al. 1999; Despres et al. 2000). TFA intake is also thought to have an undesirable effect on lipid and fatty acid metabolism in the liver as well as in the adipocyte, to trigger pro-inflammatory processes, and to perturb vascular function (Mozaffarian et al. 2006). All of this has led regulatory agencies and health organizations in many countries to propose limits for TFA consumption. In Denmark, TFA from industrial sources have been banned and are no longer found in the foods consumed by the population (Stender and Dyerberg 2003). In Canada, monitoring of various foods since 2006 has shown a drastic reduction in TFA content (Ratnayake et al. 2009a). This is largely owing to recommendations of the Trans Fat Task Force to limit the TFA content of vegetable oils and soft, spread-

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able margarines to 2% of the total fat content and to limit the TFA content for all other foods to 5% of the total fat content, including ingredients sold to restaurants (Ratnayake et al. 2009b). As a result, the estimated average intake of TFA in Canada significantly dropped from an estimated 8.4 g·day–1 in the mid-1990s to 3.4 g·day–1 (or 1.4% food energy) in 2008 (Ratnayake et al. 2009a). TFAs are not only found in industrially produced products but are also present naturally in foods from ruminants (rTFA). Although small in relative terms, the proportion of total dietary TFA coming from “natural” sources (mostly ruminant milk and meat) is not trivial (Gebauer et al. 2011). In fact, this proportion can be as high as 90% in countries where TFA from industrial sources have been eliminated (Stender and Dyerberg 2003). Beef contains approximately 1 g of rTFA per serving, whereas cheese and whole milk contain approximately 0.2 g of rTFA per serving (Gebauer et al. 2011). Denmark, France, Germany, and the Netherlands are the countries in which the estimated consumption of rTFA is the highest (1.2–1.7 g·day–1). The rTFA intake in other countries such as New Zealand, Australia, Sweden, Italy, and USA has been estimated at 1 g·day–1 (Gebauer et al. 2011). Unlike TFA from industrially hydrogenated vegetable oils (iTFA), the effects of rTFA are less well known. Meta-analysis of cohort studies has suggested that, unlike iTFA, intake of rTFA was not associated with an increased risk of CHD (Bendsen et al. 2011). A few well-controlled clinical trials have investigated the impact of rTFA on blood lipids and other CHD risk factors. We have shown in a randomized, crossover trial in healthy men that consumption of 10 g·day–1 or more of rTFA (corresponding to 3.7% of total energy intake) was associated with increased LDL-c concentrations similar to the one observed after consumption of 10 g·day–1 of iTFA (Motard-Belanger et al. 2008). However, achieving 10 g·day–1 of rTFA is impossible in real life because the natural content of rTFA in foods is too low. A more “moderate” intake of rTFA, i.e., 4 g·day–1 or 1.5% of daily energy, had no impact on blood lipids in these men (Motard-Belanger et al. 2008). A 4 g·day–1 intake in rTFA would be achieved in “real life” by the cumulative intake of 4 servings of cheese (4 × 50 g, 33% fat), 2 servings of milk (2 × 250 mL; 3.25% fat), one serving of yogurt (175 g; 3.25% fat), and 8 teaspoons of butter (8 × 5 mL). One would accept that this is still a hardly achievable intake of rTFA when consumed under normal circumstances. Women have been greatly under-represented in the few clinical studies on rTFA published to date. We have therefore also investigated how increasing the intake of rTFA by approximately 1.2% of daily energy (approximately 3 g·day–1) affects plasma lipid levels and other risk factors in women (Lacroix et al. 2012). This randomized, double-blind crossover study involving 62 women was powered to detect very small changes in plasma LDLcholesterol. After a 4-week consumption of rTFA, there was no change in LDL-cholesterol or in apolipoprotein B concentrations (Lacroix et al. 2012). rTFA intake at this level also had no impact on blood pressure and C-reactive protein. Plasma HDL-cholesterol concentrations were significantly reduced by 2.8% but average values (1.6 mmol·L–1) remained relatively high at the end of the rTFA diet in this sample of healthy women. Thus, data available to date from epidemiological studies as well as from clinical trials suggest that current intake of rTFA is unlikely to have a significant impact on CHD risk (Gebauer et al. 2011). However, we stress that very few studies have investigated the impact of rTFA on CHD risk factors compared with the number of studies providing information on iTFA. Thus, more controlled trials are needed to confirm current hypotheses.

Summary In summary, speakers showcased cutting edge lipid research spanning fundamental research on omega-3 PUFA, TFA, and pediatrics to government regulatory health claims. In addition, the speakers highlighted emerging areas such as nutrigenomics that Published by NRC Research Press

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will bring forth continued advancements in our understanding of lipids in nutrition and health in the not too distant future. Nutrigenomics has shed new light on the metabolism of omega-3 and omega-6 fatty acids in humans and highlights the potential for continued advancement of personalized nutrition. Omega-3 fatty acids remain very topical and both plant and marine based forms have heart healthy benefits and contribute beneficially to other chronic diseases and in the development of young children. In recent years, there have been significant changes in the regulatory framework in Canada that has led to the approval of several health claims related to specific dietary components and effects on cholesterol. A health claim for unsaturated fats and their beneficial effects on lowering cholesterol was approved in 2012. Trans fats from industrial sources are recognized for their negative health effects. There is growing distinction between naturally and synthetic forms of trans fats, which have different biological and health effects. There was much discussion around heart health and cholesterol as a key biomarker, but the impact of different types of fatty acids on diseases including diabetes, cancer, inflammatory diseases, and mental health are also advancing rapidly, which may be the focus of future meetings.

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Harper, C.R., Edwards, M.C., and Jacobson, T.A. 2006. Flaxseed oil supplementation does not affect plasma lipoprotein concentration or particle size in human subjects. J. Nutr. 136(11): 2844–2848. PMID:17056811. Harris, W.S., Mozaffarian, D., Rimm, E., Kris-Etherton, P., Rudel, L.L., Appel, L.J., et al. 2009. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation, 119(6): 902–907. doi:10.1161/CIRCULATIONAHA.108.191627. PMID: 19171857. Health Canada. 2007. Status of Disease Risk Reduction Claims in Canada. Available from http://www.hc-sc.gc.ca/fn-an/label-etiquet/claims-reclam/ permitted_claims-allegations_autorisees-eng.php. Health Canada. 2012a. Health Claim Assessments-Substantiation of Health Claims. Available from http://www.hc-sc.gc.ca/fn-an/label-etiquet/claimsreclam/assess-evalu/index-eng.php. Health Canada. 2012b. Nutrition and Health Claims. Available from http:// www.hc-sc.gc.ca/fn-an/label-etiquet/claims-reclam/index-eng.php. Health Canada and The Bureau of Nutritional Sciences. 2012. Summary of Health Canada's Assessment of a Health Claim about the Replacement of Saturated Fat with Mono- and Polyunsaturated Fat and Blood Cholesterol Lowering. Available from http://www.hc-sc.gc.ca/fn-an/alt_formats/pdf/label-etiquet/ claims-reclam/assess-evalu/sat-mono-poly-fat-gras-eng.pdf. Health Canada and The Office of Nutrition Policy and Promotion. 2006. Canadian Community Health Survey Cycle 2.2, Nutrition (2004)—A Guide to AcPublished by NRC Research Press

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