Fatty Acids in Corn Oil

CHAPTER 6

Fatty Acids in Corn Oil: Role in Heart Disease Prevention Marie-Pierre St-Onge1 and Alexane Travers2 1

Department of Medicine, College of Physicians and Surgeons, Institute of Human Nutrition, Columbia University, New York, NY, USA 2Institut AgroParisTech, Paris, France

Introduction Consumption of nonhydrogenated vegetable oils has been recommended for cardiovascular health. In fact, partial hydrogenation of those oils, whether to improve their stability or cooking properties, leads to the production of trans fatty acids (TFAs) that have been associated with adverse health effects, such as increased risk of stroke and cardiovascular disease (Chien et al., 2013; Kiage et al., 2014). Industrial TFAs have been shown to exert those detrimental health effects (Lichtenstein, 2014), and various health agencies have sought their ban from the American diet (Brownell and Pomeranz, 2014). Indeed, it is unquestionable that TFAs increase the risk of coronary heart disease and metabolic syndrome (Vannice and Rasmussen, 2014). TFAs arise from the hydrogenation of polyunsaturated fatty acids (PUFAs). In fact, high intakes of partially hydrogenated vegetable oils, a source of TFA, are associated with higher plasma C-reactive protein (CRP), tumor necrosis factor α (TNF α), and interleukin 6 (IL-6) compared to the lowest intake (Esmaillzadeh and Azadbakht, 2008). From the mounting evidence of the adverse health effects of TFAs, the U.S. Food and Drug Administration (FDA) passed a regulation in 2003 requiring manufacturers to list the TFA content of their food products on the Nutrition Facts Panel, allowing TFA contents of less than 0.5 g to be listed as 0 g (FDA, 2014). This rule was effective in January 2006. Consequently, New York City was the first US city to ban trans fats from commercial establishments in 2006, and the state of California followed in 2008 (Brownell and Pomeranz, 2014). Corn oil is a logical replacement for hydrogenated vegetable oils, the major source of TFA, since it is a naturally stable oil. However, there is some confusion regarding which vegetable oils should be recommended for daily consumption based on their fatty acid profiles and effects on cardiovascular disease risk markers. We will review

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132 Chapter 6 Table 6.1: Fatty acid profile of common animal and vegetable fats Nutrient/100 g

Corn Oil

Energy (kcal) Total fat (g) PUFA (g) MUFA (g) SFA (g) Vitamin E (mg α-tocopherol)

900 100 54.68 27.58 12.95

Soybean Oil Safflower Oil Canola Oil Sunflower Oil Palm Oil 884 100 57.74 22.78 15.65 8.18

884 100 74.62 14.36 6.20 34.10

884 100 28.14 63.28 7.37 17.46

884 100 28.96 57.33 9.01 41.08

884 100 9.30 37.00 49.30 15.94

Butter 717 81.1 3.04 21.02 51.37 2.32

health evidence to determine whether corn oil should be considered a healthy choice for cardiovascular health effects. Corn oil has a high smoke point, providing desirable cooking properties. In addition, corn oil has an attractive fatty acid profile. The majority of the fatty acids found in corn oil are PUFAs (54.7% of total fatty acids), followed by a moderate amount of monounsaturated fatty acids (MUFAs) (27.6% of total fatty acids) and some saturated fatty acids (SFAs) (13% of total fatty acids) (Table 6.1). Corn oil’s major PUFA is linoleic acid. Moreover, corn oil is a good source of vitamin E (1.9 mg of α-tocopherol per tablespoon, equivalent to 10% of the recommended daily value). It is well accepted that n-6 PUFA, and particularly linoleic acid, has cholesterol-lowering effects. Studies have shown that replacing carbohydrates and SFAs with PUFAs reduces low-density lipoprotein cholesterol (LDL-C), and linoleic acid has been described as the most potent cholesterol-lowering nutrient (Sacks and Campos, 2006). A meta-analysis of 60 controlled trials showed that replacing carbohydrates with n-6 PUFAs was predictive of the greatest reduction in total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) ratio and LDL-C relative to other fatty acids (Mensink et al., 2003). Another meta-analysis of 72 studies showed that replacing SFAs with PUFAs substantially reduced TC, LDL-C, and TC:HDL-C (Hodson et al., 2001). Evidence in humans therefore suggests a cardioprotective effect of PUFAs; indeed low linoleic acid levels are associated with higher risk of cardiovascular events (Czernichow et al., 2010). This degree of evidence has led the American Heart Association to report that consumption of 5 10% of energy from n-6 PUFAs decreases the risk of CVD relative to lower intakes (Harris et al., 2009). However, this may be only advisable in the primary prevention of CVD because other research has shown increased all-cause mortality and cardiovascular mortality in CHD patients assigned to an intervention that recommended increasing n-6 PUFA consumption to 15% of energy and reducing SFAs to less than 10% of energy (Ramsden et al., 2013). In that study, an increase of 5% energy from linoleic acid predicted a 29% higher risk of death from all causes and a 35% higher risk of cardiovascular death after adjusting for age, dietary cholesterol intake, body mass index, smoking, alcohol intake, and marital status. This was

Fatty Acids in Corn Oil: Role in Heart Disease Prevention 133 Corn oil consumption

Linoleic acid intakes

Plasma levels of linoleic acid

Plasma levels of arachidonic acid

Synthesis of pro-inflammatory eicosanoids

Synthesis of IL-6, TNF α, CRP

Elongation of α linolenic acid to EPA and DHA

Synthesis of anti-inflammatory eicosanoids

Incidence of cardiovascular disease

Figure 6.1 Theoretical model by which dietary linoleic acid could lead to increased inflammatory markers. Abbreviations: CRP, C-reactive protein; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IL-6, interleukin 6; TNF α, tumor necrosis factor α.

also despite a greater reduction in TC in the intervention group compared to the control group not receiving dietary recommendations. Despite their benefit for cholesterol reduction, there has been some concern regarding the potential inflammatory effect of n-6 PUFAs, specifically. A main concern involves the biochemical pathways in which linoleic acid is involved that lead to pro-inflammatory cytokines (Figure 6.1). Linoleic acid is a precursor for arachidonic acid via chain elongation. Series of chain elongations and desaturations from arachidonic acid give rise to pro-inflammatory eicosanoids that can increase levels of other markers of inflammation such as IL-6, TNF α, and CRP, which are associated with increased incidence of cardiovascular disease (Johnson and Fritsche, 2012; Vannice and Rasmussen, 2014). Another concern is the possibility that flooding the elongation/desaturation system with linoleic acid would lead to a reduced potential for elongation and desaturation of α-linolenic acid, whose pathway gives rise to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), two long-chain n-3 PUFAs that are well known for their

134 Chapter 6 anti-inflammatory effects (Johnson and Fritsche, 2012). The result would then be enhanced production of pro-inflammatory eicosanoids and cytokines at the expense of antiinflammatory eicosanoids. However, this theoretical model has not consistently been shown in human studies. In this chapter we will review some of the most recent literature regarding this controversial effect of n-6 PUFAs on markers of inflammation in addition to a brief update on the effects of corn oil on lipid profile. Because linoleic acid is the most abundant fatty acid in corn oil, studies of linoleic acid will supplement the literature on corn oil to achieve this objective.

Effects of Corn Oil/Linoleic Acid on Plasma Lipid Profile We have previously evaluated the cardiovascular health effects of corn oil consumption (St-Onge and Singh, 2009). Most recently, Jones et al. (2014) published results of a multicenter, controlled feeding study testing the cardiovascular health effects of diets differing in ratios of n-9, n-6, and n-3 fatty acids. Participants were selected to have at least one CHD risk factor. Five different diets were administered for 4 weeks each in a randomized, double-blind, crossover design: canola oil, high oleic canola oil with DHA, high oleic canola oil, corn oil and safflower oil mix, and flaxseed oil and safflower oil mix. The safflower oil mix diets were rich in n-6 PUFAs, the corn oil mix being the richest in linoleic acid. At endpoint, lipid profiles were compared between diets. The canola oil with DHA diet resulted in the highest TC, LDL-C, HDL-C, and lowest triglyceride concentrations; all values were significantly higher than after the corn oil/safflower oil diet. The two safflower oil-containing diets resulted in the greatest reductions in TC with the corn oil/safflower oil diet producing the greatest reduction in LDL-C from baseline. However, the canola oil with DHA diet, due to beneficial effects on HDL-C and triglycerides, resulted in the best Framingham score reduction for cardiovascular disease risk prediction. Studies of the relationship between corn oil and CVD risk focus mostly on the major, traditional, marker of CVD risk: the lipid profile. The lipid profile has been the traditional therapeutic target recommended by the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) (Greenland et al., 2010). Nevertheless, this is not the only risk factor for CVD. Novel risk factors have emerged, such as coagulation and inflammatory markers, and oxidative status (Ikonomidis et al., 2009). Inflammation may be a possible mediating mechanism through which dietary intakes of TFAs affect chronic disease risk (Micha and Mozaffarian, 2008) and the recommendation of the ACCF/AHA is to include the assessment of CRP to inform treatment decisions if risk-based treatment is uncertain after assessment of the 10-year risk of first event (Goff et al., 2014). The remainder of this chapter will focus on the effects of corn oil/linoleic acid intake on inflammatory markers.

Fatty Acids in Corn Oil: Role in Heart Disease Prevention 135

Effects of Corn Oil on Inflammation As mentioned earlier in this chapter, there is controversy regarding the inflammatory effects of n-6 PUFAs. When Esmaillzadeh and Azadbakht (2008) examined the diets of Tehranian women, those in the highest quintile of nonhydrogenated vegetable oil intake had lower circulating CRP, TNF α, serum amyloid A, and soluble intercellular adhesion molecule 1 (sICAM-1). Included in the category of nonhydrogenated vegetable oils were corn oil and soybean oil (two PUFA-rich oils) and sunflower oil, canola oil, and olive oil (three MUFA-rich oils). Therefore, from this observational study, it is unknown whether the effect of nonhydrogenated vegetable oils on inflammatory markers is the result of MUFA or PUFA intakes. Very few studies have specifically examined the effects of corn oil consumption on markers of inflammation. Available studies are acute (Bogani et al., 2007; Papageorgiou et al., 2011; Tousoulis et al., 2010) and most have very small sample size (,10/group) (Bogani et al., 2007; Tousoulis et al., 2010). Bogani et al. (2007) used a randomized, crossover study to assess the effects of bolus intakes of 50 mL extra-virgin olive oil, olive oil, or corn oil on inflammatory markers. Participants were 12 healthy, young, normal-weight men who were studied after 5 days of a low-phenolic diet. Thromboxane B2 and leukotriene B4 were decreased with extra-virgin olive oil intake relative to olive oil and corn oil over a 6 h postprandial period. Antioxidant capacity did not change postprandially after corn oil intake, whereas there was a significant increase following extra-virgin olive oil intake. In similar parallel arm studies, Papageorgiou et al. (2011) and Tousoulis et al. (2010) tested acute effects of extra-virgin olive oil, soybean oil, corn oil, and cod-liver oil on markers of inflammation, endothelial function, and oxidative stress in young, normal weight individuals. Participants were randomly assigned to one of the test oils. Each test oil was administered as a 50 mL bolus ingestion, not as part of a mixed meal, and measurements were taken over a 3-h period postingestion. There was no effect of oil type on soluble vascular cell adhesion molecule 1 (sVCAM-1), but all oils decreased sICAM-1 and all, except for corn oil, decreased TNF α (Papageorgiou et al., 2011). Moreover, corn oil decreased reactive hyperemia (Tousoulis et al., 2010). Authors concluded that extra-virgin olive oil, soybean oil, and cod-liver oil exert similar anti-inflammatory effects (Papageorgiou et al., 2011), but corn oil leads to impaired endothelial function (Tousoulis et al., 2010). These results have been somewhat contradicted in an in vitro study showing that corn oil is pro-inflammatory (Ion et al., 2011). Jurkat T leukemia cells treated with corn oil for 72 h had increased expression of IL-8 and IL-8 receptor B, among others, compared to nontreated cells. However, a study in rats showed that vegetable oils, including corn oil, prevent oxidative damage and enhanced anti-inflammatory effects of indomethacin administration (Odabasoglu et al., 2008).

136 Chapter 6 Based on these studies, the inflammatory properties of corn oil are unclear. Different results are obtained based on the type of study: in vitro, animal, or human. Further, longer-term studies are needed to determine whether corn oil consumption has anti-inflammation effects. Issues related to comparison diet and participant characteristics would also need to be clarified.

Effects of Linoleic Acid on Inflammation There has been somewhat more research on the inflammatory effects of linoleic acid than those of corn oil. Since linoleic acid is the most abundant fatty acid in corn oil, such studies can provide additional information regarding the effects of corn oil on inflammatory markers. Poudel-Tandukar et al. (2009) examined the association between PUFA intake and CRP levels in Japanese employees. Using a self-administered diet history questionnaire to assess intakes over the previous month, the authors found an inverse relationship between dietary linoleic acid and CRP in men but not women. In men, CRP was 43% lower in the highest linoleic acid intake group compared with the lowest intake group. In the United States, data from the Physicians’ Health Study and the Nurses’ Health Study were also used to assess relationships between PUFA intakes and inflammatory markers (Pischon et al., 2003). In that study, linoleic acid intakes were not related to any inflammatory marker: CRP, IL-6, soluble TNF receptor 1 and receptor 2. However, in those with high n-6 PUFA intakes, there was a very strong inverse association between EPA and DHA and TNF receptor 1 and receptor 2 that was not observed in those with low linoleic acid intakes. Individuals with the highest EPA plus DHA and linoleic acid intakes had the lowest TNF receptor 1 and receptor 2 levels, whereas those with high linoleic acid and low EPA plus DHA intakes had the highest levels of those receptors. The authors concluded that, contrary to some beliefs, n-6 PUFAs do not appear to antagonize the effects of n-3 PUFAs on inflammatory markers. These data support observations from Djousse et al. (2001) that high intakes of linoleic acid and α-linolenic acid are associated with a lower prevalent odds ratio of coronary artery disease in men and women and that combined intakes have synergistic effects. One longitudinal study assessed the association between PUFA intakes and CRP measured 12 years later (Julia et al., 2013). In that study, there was an inverse association between linoleic acid and CRP, and the authors concluded that linoleic acid has anti-rather than pro-inflammatory effects. Interestingly, the extent of the association with CRP was similar for n-3 and n-6 PUFAs. Those observational studies therefore show that linoleic acid is either neutral or has a beneficial effect on markers of inflammation. Such conclusions can also be drawn from the results of an intervention study (Thies et al., 2001). Participants were randomized to groups consuming encapsulated oil blends rich in

Fatty Acids in Corn Oil: Role in Heart Disease Prevention 137 α-linolenic acid, linoleic acid, arachidonic acid, DHA, or EPA. Participants were required to take three capsules of 445 mg oil blends three times daily for 12 weeks. The authors found no effects of treatment on TNF α, IL-6, sICAM-1, or serum E-selectin. EPA only decreased sVCAM-1 levels. The authors concluded that moderate levels of n-6 and n-3 PUFAs do not influence circulating inflammatory cell numbers and that increasing consumption of n-6 PUFAs does not have adverse effects. Dietary linoleic acid intakes therefore do not seem to represent the theoretical process of eicosanoid production presented in Figure 6.1. This seems to relate to the poor association between dietary PUFAs and circulating PUFA levels. Indeed, Harris et al. (2009) reported in their position statement that wide variations in linoleic acid do not alter plasma levels of arachidonic acid so much. James et al. (1993) have shown that over a range of linoleic acid intakes of 2.5 17.5% of energy, plasma levels of linoleic acid, but not arachidonic acid, were reflective of intakes. They concluded that reductions in linoleic acid consumption could reduce plasma linoleic acid levels, but this would not be an effective strategy to reduce arachidonic acid levels in tissues. Furthermore, the relationship between plasma levels of fatty acids and inflammatory markers is controversial. Ferrucci et al. (2006) reported that participants in the two lower quartiles of plasma linoleic acid had lower soluble IL-6 receptors than those in the upper two quartiles. In addition, total n-6 PUFAs, of which approximately 75% were linoleic acid, were inversely associated with IL-6, IL-1 receptor α, TNF α, and CRP, and positively related to soluble IL-6 receptor and IL-10 after adjusting for age and sex. However, when n-3 PUFAs were included in regression models, most associations between n-6 PUFAs and inflammatory markers became nonsignificant. On the other hand, Soto-Vaca et al. (2013) showed that treating coronary arterial smooth muscle and endothelial cells with linoleic acid decreased IL-6. They also concluded that linoleic acid proved to be the least proinflammatory fatty acid of the 14 relevant fatty acids studied.

Conclusions Recent literature on the effects of corn oil on markers of inflammation is limited. Those studies indicate that acute intakes of corn oil do not affect short-term (up to 6 h) inflammatory status or have similar effects as other vegetable oils. In vitro and animal studies showed differing results. However, chronic intakes of linoleic acids, the most abundant fatty acid in corn oil, as reflected from self-report diet history or questionnaires, seem to either have neutral or beneficial effects on markers of inflammation. Similarly, administration of oils rich in various PUFAs does not affect inflammatory markers over a range that would be plausible for human consumption. Therefore, to date, there is no information to support the view that linoleic acid has adverse pro-inflammatory effects; rather, studies have shown a neutral or anti-inflammatory effects associated with its consumption.

138 Chapter 6 Future studies are needed to determine the inflammatory effects of corn oil. Corn oil is comprised of not only linoleic acid, and it is possible that its various components can mitigate potential health effects. For example, corn oil is rich in plant sterols (Ostlund et al., 2002), which are well known to reduce cholesterol concentrations (St-Onge and Jones, 2003), and in vitamin E, a potent antioxidant. It is possible that synergistic effects between individual phytonutrients may affect the overall cardiovascular health effects of corn oil. Moreover, other dietary components, such as intakes of n-3 PUFAs, could be important in the overall assessment of the health effects of corn oil.

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