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Experimental Gerontology xxx (2014) xxx–xxx
EXG-09487; No of Pages 6
Contents lists available at ScienceDirect
Experimental Gerontology
j ourna l homepage: www.e lsev ie r .com/ locate /expgero
High corn oil dietary intake improves health and longevity of aging mice
F
Hongwei Si a,⁎, Longyun Zhang a, Siqin Liu a, Tanya LeRoith b, Carlos Virgous c
a Department of Family and Consumer Sciences, Tennessee State University, Nashville, TN 37209, United Statesb Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, United Statesc Animal Care Facility, Meharry Medical College, Nashville, TN 37208, United States
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Abbreviations: BW, bodyweight; EFAs, essential fattyGSR, glutathione-disulfide reductase; GSH, glutathioneHDL, high-density lipoprotein;HF, high cornoil diet; IFN-γkin; KC, keratinocyte chemoattractant; LDL, low-density lichemoattractantprotein-1;MUFA,monounsaturatedfattyunsaturatedfattyacid;ROS,reactiveoxygenspecies;SFA,saide dismutase; TNFα, tumor necrosis factor-α; YC, youth c⁎ Corresponding author.
E-mail address: [email protected] (H. Si).
http://dx.doi.org/10.1016/j.exger.2014.09.0010531-5565/© 2014 Published by Elsevier Inc.
Please cite this article as: Si, H., et al., High cdx.doi.org/10.1016/j.exger.2014.09.001
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Article history:Received 15 July 2014Received in revised form 29 August 2014Accepted 2 September 2014Available online xxxx
Section Editor: Holly M Brown-Borg
Keywords:Corn oilAging miceLongevityHealth
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Corn oil has been recommended as a replacement for saturated fats because of its high levels of poly- andmono-unsaturated fatty acids. In the present study,we testedwhether very high levels of corn oil (58.6% fat-derived cal-ories, FDC) intake improve health and longevity of aging mice. Twelve month old male C57BL/6 mice were fed anormal diet (10% FDC of corn oil, N) or a high fat diet (58.6% FDC of corn oil, HF) for 13–15 months. Our resultsshow that aHFdiet significantly increased the longevity of the agedmice (at 25 months of age, 53.8% ofmice diedin the N group, whereas the mortality rate was only 23.2% in the HF group). High corn oil also reversed aging-increased blood lipids including triglyceride, total cholesterol and LDL. Similarly, high corn oil intake overturnedaging-raised pro-inflammatory markers including IL-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1) inthe blood. In addition, corn oil intake reversed aging-damaged rotarod performance and liver function. Interest-ingly, the HF group was significantly heavier than the N group (53.6 g/mouse vs. 41.3 g/mouse); however, bothHF and N groups had the same calorie intake (12.48 kcal/d/mouse vs. 12.24 kcal/d/mouse). Although, the HFgroup's food consumption was lower than that of the N group (2.4 g/d/mouse vs. 3.4 g/d/mouse). These resultssuggest that if total calorie consumption stays in the normal range, very high levels of corn oil intake improvehealth and longevity of aging mice.
© 2014 Published by Elsevier Inc.
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RRE1. Introduction
High saturated fat diets are well associated with obesity prevalenceand the increased risk of cardiovascular disease, diabetes and cancer.Reducing saturated fats from the diet is recommended to eliminateWestern diet-induced health problems. The common alternatives ofanimal (saturated) fats for humans are plant oil, including soybean oil,peanut oil and corn oil because of the high percentage of unsaturatedfat acids.
Corn oil is composed mainly (99% of the refined or 96% of the crudeoil) of acylglycerols (mono-, di- and primarily tri-), and has 59% poly-unsaturated (PUFA), 24% monounsaturated (MUFA) and 13% saturatedfatty acid (SFA). The PUFA to SFA ratio (P/S) is about 4.6. Corn oil has oneof the highest PUFA levels after sunflower, safflower, walnut and wheatgerm oil (Landers and Rathmann, 1981). The primary PUFA is linoleicacid (C18:2n−6), with a small amount of linolenic acid (C18:3n−3)
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acids; FDC, fat-derived calories;; H&E, hematoxylin and eosin;, interferongamma; IL, interleu-poprotein;MCP-1, macrophageacid;N,normaldiet;PUFA,poly-turatedfattyacid;SOD,superox-ontrol.
orn oil dietary intake improv
giving a n−6/n−3 ratio of 83. Corn oil contains a significant amountof ubiquinone and high amounts of gamma-tocopherols (vitaminE) (Dupont et al., 1990). These high contents of PUFA and vitamin Emay contribute to the health benefits of corn oil consumption.
The beneficial effects of PUFA have been extensively investigated,however, there are very few studies investigating the effects on humanhealth with long-term corn oil consumption, particularly on the olderpopulation. This is very important because corn oil is the second leadingvegetable oil consumed in the United States (USDA, 2014). Since U.S.adults age 65 and older heavily consume this high fat oil, their populationis rapidly increasing and is projected to reach 71million by 2030. The ob-jectives of the present study are to investigate the long-term health effectof high volume of corn oil consumption in aging mice and to understandthe relevant mechanisms.
2. Methods and Materials
2.1. Experimental Animals and Diets
Twelve-month old male C57BL/6 mice were purchased from theNational Cancer Institute (Bethesda, MD). Mice were housed in anenvironmentally-controlled (23 ± 2 °C; 12-h light: dark cycle) animalfacility and they were given ad libitum access to food and water. Totest the health effect of high corn oil intake, mice were randomly divid-ed into two groups (n=31) and given either a normal diet (N) or a high
es health and longevity of aging mice, Exp. Gerontol. (2014), http://
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corn oil diet (HF). Both diets are based on theAIN-93 produced by DyetsInc. (Bethlehem, PA) with two exceptions: 1) soybean oil was replacedwith corn oil and 2) the percentage of corn oil in each diet. The normaldiet has 10% fat derived calories (FDC) and the HF diet has 58% fat de-rived calories (FDC) (Reeves et al., 1993). This dose of corn oil (58%FDC) was calculated based on previous studies using high fat diet (60%FDC, 6% from soybeanoil and 54% from lard) (Sung et al., 2014). Detailedcompositions of the diets are listed in Table 1. To ensure the stability ofthe corn oil, dietswere stored at 4 °C andwere kept away from light. Thediets were replaced every week. Bodyweight (BW) and food consump-tion were monitored weekly. The general health and well-being of themice were monitored daily. If a mouse was reported as or marked assick, the criteria for euthanizing mice were independently assessed bya veterinarian adhering to the Institutional Animal Care and Use Com-mittee guidelines. Mice with a BW less than 30% of their original BWand other critical conditions including severe ulcerative dermatitis, uri-nary obstruction and abdominal masses were euthanized by inhalationof CO2 and censored. When the median for the control group wasreached, the remaining 14 mice from the control group and 12 micefrom the HF group were fasted overnight and euthanized using CO2,and their blood and tissues were collected for biochemical and physio-logical analysis. The HF group continued until the median was reached.We also collected blood and tissues from youth controlmice (12-monthold, 12 mice, YC) to compare the changes of biochemical and phy-siological analysis with the other two groups. The animal protocol wasapproved by the Institutional Animal Care and Use Committee atMeharry Medical College.
2.2. Measurements of Serum Biological Markers and Hepatic Antioxidants
Serum total cholesterol, HDL-cholesterol, and triglycerides in micewere measured using a PTS CardioChek Blood Analysis Meter (MariaStein, OH) according to the manufacturer's instructions and our previ-ous report (Si et al., 2011). LDL-cholesterol was calculated using the for-mula from the manual of the analysis meter: LDL-cholesterol = totalcholesterol − HDL-cholesterol − triglyceride / 5. Serum cytokinesand chemokines including interleukin (IL)-6, IL-1β, IL-10, tumor necro-sis factor-α (TNFα), keratinocyte chemoattractant (KC), monocyte che-motactic protein 1(MCP-1) and interferon gamma (IFN-γ) were testedby a Luminex mouse cytokine array assay (Capital Biosciences, MD) aspreviously described (Si et al., 2011; Veenbergen et al., 2010). The activ-ity of glutathione-disulfide reductase (GSR) in the liver was measuredas we previously described (Si et al., 2011).
2.3. Pathological Analysis
Fresh livers were fixed in 10% phosphate buffered neutral formalin,embedded in paraffin, cut at thicknesses of 5 μm, and then stainedwith hematoxylin and eosin (H&E) for histological examination ofhepatic lesions. Three sections from each mouse were examined. The
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Table 1Diet composition and energy distribution.
Ingredient Normal diet (N) High fat diet (HF)
g/kg kcal/kg g/kg kcal/kg
Casein 140 501.2 226.8 811.9L-Cystine 1.8 7.2 3 12.0
Sucrose 100 400 100 400Corn starch 465.7 1676.52 75.7 272.52Dyetrose 155 589 155 589Corn oil 40 360 340 3060Cellulose 50 0 50 0Mineral mix #210050 35 29.4 35 30.8Vitamin mix #310025 10 38.7 10 38.7Choline bitartrate 2.5 0 2.5 0Total 1000.00 3602.02 1000.00 5214.96
Please cite this article as: Si, H., et al., High corn oil dietary intake improvdx.doi.org/10.1016/j.exger.2014.09.001
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pathological alterations in the liver were scored according to the levelsof vacuolar changes (hydropic degeneration or lipidosis) in hepatocytes(1 = 0–10%, 2 = 10–30%, 3 = 30–50%, and 4 ≥ 50% of hepatocytesaffected).
2.4. Rotarod Test
Rotarod assay, a simple and accurate approach to examining age-related changes in balance and motor coordination (Baur et al., 2006),was performed using the rotarod apparatus (Med Associates, St. AlbansVT) at 14 and 25 month old mice to examine their ability to remain onan revolving rod (Coyle et al., 2008). Briefly, a mouse was briefly placedin a separate lane of a rotarod with an accelerating speed (2–20 rpm)until the mouse fell off the rod. The length of time and speed of themouse which stayed on the rod were recorded.
2.5. Statistical Analysis
The longevity curves were plotted using the Kaplan–Meier methodincluding all available mice at each time point (Baur et al., 2006), andthe Logrank test was applied to compare the distributions of the differ-ent groups. The results from the pathological analysis of the liver wereanalyzed using the Kruskal–Wallis test, and significant differencesbetween treatment groups were further analyzed using the Mann–Whitney-U test. All other data were analyzed with one-way ANOVAand significant differences between treatment groups were furtheranalyzed using the t-test. P-values less than 0.05 were considered tobe statistically significant (*, P b 0.05; **, P b 0.01).
3. Results
3.1. Longevity
At 25 months of age, 53.8% of mice had died in theN group,whereasthemortality rate was only 23.2% in the HF group (P= 0.02, Fig. 1). Themedian for the HF groupwas reached twomonths later at 27 months ofage. While the sample size (n = 31/group) was relatively small for atypical longevity study, we think that the observed effects of high cornoil on the longevity of aging mice is a real action of this compound be-cause such a large difference between the two groups was unlikelydue to random variation.
3.2. Similar Energy Intake
Although the average BW in the HF group was significantly higherthan that in the N group as shown in Fig. 2A, the food consumptionin the HF group was significantly lower than that in the N group
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Fig. 1. Longevity curve in normal diet (N) and high corn oil diet (HF)mice for 13–15 months.There Q1initially was 31 mice/group. *P b 0.05.
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3H. Si et al. / Experimental Gerontology xxx (2014) xxx–xxx
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(Fig. 2B). Thismay be a result of the texture of theHF diet, which has theconsistency of paste. Some days an oily liquid would form on the top ofthe rodent feeding jars, while the N diets were typical pellets. Interest-ingly, there was no significant difference in energy intake betweenthese two groups (Fig. 2C).
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ORRE3.3. Maintained Rotarod PerformancePhysical activity and locomotor function continuously diminishingwith aging (Baur et al., 2006; Yankner et al., 2008) and although cornoil increased longevity, it is important to know whether the quality oflife was maintained. We evaluated the ability to perform on a rotarod,a classic method of testing balance and motor coordination. While thetime on the rod was significantly decreased as mice aged in the Ngroup (decreased from 115 s at month 14 to 80 s at month 25), the
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Fig. 3. Corn oil maintained rotarod performance in both normal diet (N) and high corn oildiet (HF) mice at 14 and 25 months of age. Data are means ± SE, n = 12 mice/group.*P b 0.05.
Please cite this article as: Si, H., et al., High corn oil dietary intake improvdx.doi.org/10.1016/j.exger.2014.09.001
EHF group maintained their motor skills until they were 25 months ofage (Fig. 3).
3.4. Improved Hepatic Pathology
Histological examination of liver sections stained with hematoxylinand eosin revealed a loss of cellular integrity and the accumulation oflarge lipid droplets in the livers of theN group, but theHFgroup reducedthe size of intracytoplasmic lipid vacuoles. Blinded scoring of the liversections for overall pathology on a scale of 0–4 (with 4 being the mostsevere) gave mean values of 2.5 for the N group, 1.8 for the HF groupand 0.8 for the YC group (Fig. 4).
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3.5. Lowered Serum Lipids
Circulating lipid abnormalities are increasingly recognized asplaying an important role in the aging process and age-related dis-orders such as diabetes and vascular dysfunction (Labinskyy et al.,2006). Compared to the YC group, serum triglyceride, total cholesteroland LDL-cholesterolwere significantly increased in theNgroup; however,all these three serum lipids were reversed in the HF group as shown inTable 2.
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3.6. Decreased Serum Inflammatory Cytokines
Consistent with observations of the pathological alterations in theliver and remarkably shortened lifespan ofmice in the N group, circulat-ing levels of cytokines including IL-1β, IL-6, IFN-γ and MCP-1 were sig-nificantly elevated in the N group compared to those in the YC group(Table 3). However, dietary consumption of corn oil significantly re-duced these pro-inflammatory markers (Table 3), indicating that cornoil may suppress chronic inflammation caused by aging. In addition,GSR activity in the livers of the N group was significantly decreased
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Fig. 4. Corn oil improved hepatic pathology in aging mice. Hematoxylin and eosin stained slides of liver (three sections from each mouse) from young control (YC), normal diet (N) andhigh corn oil diet (HF) mice were scored and the number of mice at relevant categories based on the levels of vacuolar change (hydropic degeneration or lipidosis for the liver)Q2 wasreported. A set of representative images and bar graphs (means ± SE, n = 12–14/group) were shown. The arrows point to intracytoplasmic lipid vacuoles. 200× magnification. Scalebar = 50 um. *P b 0.05.
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was reversed in the HF group (data no shown).
4. Discussion
Aging is well-known as an inevitable process that is physiologicallycharacterized as a progressive, generalized systematic dysfunction ofalmost or all organs, giving rise to the escalated vulnerability to environ-mental challenges and resulting in increased risks of disease and death.Indeed, aging is associated with a greatly increased metabolic and oxi-dative stress, elevated chronic, low-grade inflammation, and accumu-lated DNA mutations as well as increased levels of its DNA damages(Frisard and Ravussin, 2006; Heininger, 2000a,b). It is established thatcalorie restriction delays age-associated organ disorders and increaseslongevity as well as improves inflammation and oxidative stress in awide range of species, suggesting that targeting nutrient-sensing andenergy metabolism pathways may be an effective approach to delaythe aging process and age-related diseases. In the present study, wefound that high level of corn oil (58.6% FDC) intake improved healthand longevity of aging mice, which may be associated with reversingaging-increased blood lipids and pro-inflammatory makers as well asaging-damaged rotarod performance test and liver function. To our
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Table 2Blood lipid levels (mg/dL).
Group Triglyceride Total cholesterol LDL HDL
YC 115 ± 9 197 ± 19 135 ± 22 39 ± 1N 142 ± 15 314 ± 26⁎ 240 ± 23⁎ 52 ± 7HF 124 ± 12 171 ± 15 113 ± 11 40 ± 3
Values are means ± SE (n = 12–14 per group).⁎ P b 0.05.
Please cite this article as: Si, H., et al., High corn oil dietary intake improvdx.doi.org/10.1016/j.exger.2014.09.001
knowledge, the present study is the first study that shows that if totalcalorie intake is kept in the normal range, long-term very high level ofcorn oil intake can improve health and increase longevity of agingmice.
A large body of evidence indicates that increased generation of reac-tive oxygen species (ROS)which are chemically reactivemoleculeswithmost of them containing oxygen and unpaired electrons is one of themajor triggers of aging. There is a strong correlation between chrono-logical age and the levels of ROS generation and oxidative damage oftissues. ROS are primarily produced bymitochondria during energy pro-duction (about 2% of total oxygen consumption was funneled to ROS)(Chance et al., 1979). Extra amounts of ROS induces oxidation of fattyacids and proteins and causes oxidative damage of DNA that may leadto cellular senescence, functional alterations, and pathological condi-tions (Harman, 1972; Linnane et al., 1989). This extra amount of ROSis deactivated to water and oxygen by endogenous enzymes includingsuperoxide dismutase (SOD), catalase or glutathione peroxidases(Chang et al., 2004). Endogenous antioxidant glutathione (GSH) and ex-ogenous antioxidants including vitamins C and E are also important ROSscavengers. Reducing ROS is proposed as a leading strategy to delayaging and related degenerative diseases. Corn oil is one of the highestnatural sources of vitamin E (62.01 mg/100 g oil) and is just a littleless than cottonseed oil (62.37 mg/100 g oil). This high content of vita-min E may prevent aging-increased ROS and extend the lifespan ofaging mice. This is supported by our results showing that a decreasedGSR activity, a critical endogenous antioxidant enzyme, was reversedby corn oil intake (data not shown).
Aging-induced ROS also contributes to low-grade chronic inflamma-tion (Brod, 2000), a crucial player of the process of aging and age-related diseases in older adults. Indeed, chronic pro-inflammatorymarkers including IL-6, MCP-1 and TNF-α are consistently elevatedwith age in the absence of acute infection or other physiological stress(Ferrucci et al., 2005). Consequently, the sustained increases of these
es health and longevity of aging mice, Exp. Gerontol. (2014), http://
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t3:1 Table 3t3:2 Serum inflammatory cytokines (pg/ml).
t3:3 IL-1β IL-6 IL-10 IFNγ TNFα KC MCP-1
t3:4 YC 26.3 ± 10.8 17.5 ± 6.7 1.9 ± 0.0 43.9 ± 10.2 9.1 ± 3.9 42.2 ± 16.2 62.2 ± 15.2t3:5 N 43.4 ± 15.9⁎ 57.7 ± 11.6⁎ 4.9 ± 1.0 110.0 ± 28.5⁎ 6.8 ± 2.2 43.5 ± 6.6 310.0 ± 27.5⁎
t3:6 HF 26.2 ± 8.4 20.2 ± 9.6 13.1 ± 4.0 99.0 ± 24.7 6.4 ± 2.0 55.3 ± 3.3 198.0 ± 18.3
t3:7 Values are means ± SE (n = 12–14 per group).t3:8 ⁎ P b 0.05.
5H. Si et al. / Experimental Gerontology xxx (2014) xxx–xxx
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pro-inflammatory molecules impair the function and integrity of vari-ous tissues and organs and thus accelerate aging and aging-relatedchronic diseases, although this increase is still in the sub-acute range(Chung et al., 2006). Interestingly, calorie restriction significantlyattenuates the increase of these pro-inflammatory markers while ex-tending the lifespan (Chung et al., 2006; Zou et al., 2004), suggestingthat anti-inflammatory agents may have the potential to extend ahealthy lifespan. Results from the present study show that dietary in-take of corn oil significantly reversed the increase of circulating pro-inflammatory markers including IL-1β, IL-6, IFN-γ and MCP-1 in agingmice and therefore increased longevity.
Elevated LDL-cholesterol is well known as one of the major risks ofcardiovascular disease and reducing blood LDL is recommended tolower cardiovascular disease as well as other aging-related chronic dis-eases (NCEP, 2002). Corn oil has been found to be highly effective inlowering blood cholesterol, particularly LDL-cholesterol (Ahrens et al.,1957;Hill et al., 1979). Our results are in linewith these previous studiesthat corn oil lowers LDL-cholesterol, total cholesterol and triglycer-ide. This effect may be due to the high PUFA, which is supported byevidence that corn oil is more effective than olive oil in loweringLDL-cholesterol because corn oil has higher PUFA (58.7 g/100 g oil)than olive oil (8.4 g/100 g oil) (Dupont et al., 1990; Howell et al.,1998). Corn oil has a plant sterol content of 128 mg/1000 kcal vs.66 mg/1000 kcal for olive oil, and these plant sterols can reduce choles-terol absorption from the gut which in turn lowers body pools andenhances synthesis rate through de-suppression of cellular hydroxy-methylglutaryl-CoA reductase activity (Howell et al., 1998).
A lower ratio of omega-6/omega-3 fatty acids (n−6/n−3) is recom-mended to reduce the risk of many highly prevalent chronic diseases inWestern societies (ratio of n−6/n−3 in Western diets is 15/1–16.7/1(Simopoulos, 2002). Mammalian cells cannot convert omega-6 toomega-3 fatty acids because they lack the converting enzyme, omega-3 desaturase. These two classes of essential fatty acids (EFAs) are notinterconvertible, are metabolically and functionally distinct and haveopposing physiological functions. Therefore, too much omega-6 maybe detrimental for cells. Corn oil is not a good source for EFAs becausethe ratio of omega-6/omega-3 fatty acids from corn oil is 83, which ismuch higher than the recommended ratio (1/1 to 4/1) (Simopoulos,2002). However, the present study and other studies show that highcorn oil intake improves health and longevity in mice and rats(10 mg/kg/d by oral gavage) (NTP, 1994). One explanation is that ma-jority of omega-6 PUFA from corn oil is used for energy, and is notused to produce thrombi and atheromas, which are required for cardio-vascular disease development.Moreover, high levels of vitamin E (major-ly γ-tocopherol) (Elmadfa and Park, 1999) and plant sterols (0.77% byweight) (Ostlund et al., 2002) may counter the bad effects of omega-6PUFA of corn oil. For example, γ-tocopherol, the major form of vitaminE in the corn oil, and its metabolite havemore anti-inflammatory proper-ties than α-tocopherol, the predominant form of vitamin E in the tissuesand most supplements (Jiang and Ames, 2003).
Taken together, if total calorie intake is kept in a normal range,long-term very high intake of corn oil (58.6% FDC) reverses aging-increased blood lipids and circulating pro-inflammatory cytokines aswell as aging-damaged rotarod performance test and liver function,and thus increases longevity of aging mice. These health benefits ofcorn oil may result from the combinations of the high levels of PUFA,
Please cite this article as: Si, H., et al., High corn oil dietary intake improvdx.doi.org/10.1016/j.exger.2014.09.001
vitamin E and plant sterols. Therefore, corn oil, even at a high energypercentage (58%), is a favorable replacement of animal fats in thehuman diet if the total energy intake is controlled.
OFConflict of Interest
The authors declare that there are no conflicts of interest associatedwith this manuscript.
ROAcknowledgments
We are grateful for the support of the National Institute of Food andAgriculture of USDA, Evans-Allen program (TENX-1103-FS, to H. Si) forthis work.
ED
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