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Consumption of a dietary portfolio of cholesterol lowering foods improves blood lipids without affecting… Ramprasath, Vanu R; Jenkins, David J; Lamarche, Benoit; Kendall, Cyril W; Faulkner, Dorothea; Cermakova, Luba; Couture, Patrick; Ireland, Chris; Abdulnour, Shahad; Patel, Darshna; Bashyam, Balachandran; Srichaikul, Korbua; de Souza, Russell J; Vidgen, Edward; Josse, Robert G; Leiter, Lawrence A; Connelly, Philip W; Frohlich, Jiri; Jones, Peter J Oct 18, 2014

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RESEARCH Open AccessConsumption of a dietary portfolio of cholesterolblood lipids withoutConclusion: Results demonstrate that consuming a portfolio diet reduces serum total and LDL-C levels whileRamprasath et al. Nutrition Journal 2014, 13:101http://www.nutritionj.com/content/13/1/101Winnipeg, MB, CanadaFull list of author information is available at the end of the articleincreasing PS values, without altering fat soluble compounds concentrations. The extent of increments of PS withthe current study are not deleterious and also maintaining optimum levels of fat soluble vitamins are of paramountnecessity to maintain overall metabolism and health. Results indicate portfolio diet as one of the best options for CVDrisk reduction.Trial registration: clinicaltrials.gov Identifier: NCT00438425Keywords: Plant sterols, Fat soluble vitamins, Portfolio diet* Correspondence: peter_jones@umanitoba.ca1Richardson Centre for Functional Foods and Nutraceuticals, Winnipeg, MBR3T 2 N2, Canada2Department of Human Nutritional Sciences, University of Manitoba,affecting concentrations of fat soluble compoundsVanu R Ramprasath1,2, David JA Jenkins3,4,5,6, Benoit Lamarche7, Cyril WC Kendall3,5, Dorothea Faulkner3,5,Luba Cermakova8, Patrick Couture7, Chris Ireland3,5, Shahad Abdulnour3,9, Darshna Patel3,5,Balachandran Bashyam3,5, Korbua Srichaikul3,5, Russell J de Souza10, Edward Vidgen3,5, Robert G Josse3,4,5,6,Lawrence A Leiter3,4,5,11, Philip W Connelly11, Jiri Frohlich8 and Peter JH Jones1,2*AbstractBackground: Consumption of a cholesterol lowering dietary portfolio including plant sterols (PS), viscous fibre, soyproteins and nuts for 6 months improves blood lipid profile. Plant sterols reduce blood cholesterol by inhibitingintestinal cholesterol absorption and concerns have been raised whether PS consumption reduces fat solublevitamin absorption.Objective: The objective was to determine effects of consumption of a cholesterol lowering dietary portfolio oncirculating concentrations of PS and fat soluble vitamins.Methods: Using a parallel design study, 351 hyperlipidemic participants from 4 centres across Canada wererandomized to 1 of 3 groups. Participants followed dietary advice with control or portfolio diet. Participants onroutine and intensive portfolio involved 2 and 7 clinic visits, respectively, over 6 months.Results: No changes in plasma concentrations of α and γ tocopherol, lutein, lycopene and retinol, but decreasedβ-carotene concentrations were observed with intensive (week 12:p = 0.045; week 24:p = 0.039) and routine (week12:p = 0.031; week 24:p = 0.078) portfolio groups compared to control. However, cholesterol adjusted β-caroteneand fat soluble compound concentrations were not different compared to control. Plasma PS concentrations wereincreased with intensive (campesterol:p = 0.012; β-sitosterol:p = 0.035) and routine (campesterol: p = 0.034; β-sitosterol:p = 0.080) portfolio groups compared to control. Plasma cholesterol-adjusted campesterol and β-sitosterolconcentrations were negatively correlated (p < 0.001) with total and LDL-C levels.lowering foods improves© 2014 Ramprasath et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in thisarticle, unless otherwise stated.Ramprasath et al. Nutrition Journal 2014, 13:101 Page 2 of 12http://www.nutritionj.com/content/13/1/101BackgroundRandomized control trials using metabolically controlleddesigns [1-3] as well as effectiveness trials with freeliving designs [4,5] have demonstrated reductions inblood LDL-C concentrations with consumption of aportfolio diet including plant sterols (PS), soy proteins,viscous fibres and nuts. Consumption of portfolio dietfor 1 year under real world conditions by 66 participantsresulted in a 13% reduction in LDL-C levels [5]. Similarly,a recently conducted study with portfolio diet for 6 monthsusing a multicentre design across Canada showed a 13.8%reduction in LDL-C in 330 participants [4].Plant sterols are one of the components of the portfo-lio diet known for their plasma cholesterol reducingproperty. Consumption of 2 g/d of PS reduces LDL-C by13 to 16% [6]. PS are found to be effectively beneficialwhen combined with different dietary components suchas fish oil, ascorbic acid, β-glucan and psyllium [7-9] aswell as with statin drugs [10,11]. Consumption of PSmight not cause any major health concern [12], althoughsome studies have implicated increased PS concentrationsin plasma as being associated with elevated cardiovasculardisease (CVD) risk [13-17]. Other recent studies withdifferent dosages and study designs have not demon-strated that circulatory PS levels associate with risk ofCVD and hence, consumption of portfolio diet contain-ing PS may be safe and reduce risk of CVD [18-22].Cholesterol lowering effects induced by the portfoliodiet could occur through mechanisms including reducedintestinal cholesterol absorption due to PS [23], decreasedcholesterol synthesis and elevated LDL-C receptor uptakeof cholesterol in liver by soy proteins [24] increased bileacid loss by the action of dietary fibre [25] and almondsare sources of vegetable proteins, monounsaturated fatsand PS and are likely to produce their effects by a range ofmechanisms [26]. As PS act mainly by inhibiting intestinalcholesterol absorption, it might be possible that theabsorption of other fat soluble compounds such ascarotenoids, tocopherols and retinoids are compromisedby the PS containing portfolio diet consumption [27].Vitamin A is essential for multiple functions in thehuman body including maintenance of cell function,growth, vision, epithelial integrity, immune function,and reproduction. Deficiency of vitamin A leads tovision loss, increased morbidity, and mortality [28,29].Tocopherols are strong antioxidants and play importantrole in prevention of chronic diseases associated withoxidative stress such as cardiovascular disease, athero-sclerosis, and cancer [30]. Deficiency of vitamin E leadsto anemia and in addition severe deficiency could resultin neuromuscular abnormalities characterized by spino-cerebellar ataxia and myopathies [30-32].A few studies have raised concerns about reduction inthe absorption of fat soluble vitamins and carotenoidsincluding β-carotenes and α-tocopherols following PSintake [33-38]. In contrast, other interventions haveshown no changes in plasma fat soluble vitaminconcentrations with PS consumption [39-42]. Althoughcombination of PS with other portfolio dietary compo-nents showed significant reductions in plasma LDL-Cconcentrations, effects of portfolio ingredients onplasma fat soluble vitamins levels have never beenstudied. Hence our aim was to determine whether theportfolio diet with the presence of PS affects the plasmafat soluble vitamin concentrations in hypercholesterolemicparticipants. Additional objectives were to determine theextent of the increment in plasma PS concentrationfollowing a portfolio diet and determine the correlationswith other lipid markers in blood.Participants and methodsParticipantsWe have previously reported the results on the effect ofportfolio diet on CVD risk factors including plasmaLDL-C levels [4]. Detailed information on the studydesign and participant characteristics of this multi-centreclinical study has been provided [4]. Briefly, 351 hyperlip-idemic participants (137 males and 214 postmenopausalfemales) were randomized for the study at 4 differentcenters across Canada including Quebec City, Toronto,Winnipeg and Vancouver. The main inclusion criteriawere males and post-menopausal females with low tointermediate Framingham 10-year risk categories with3.50-5.31 and 3.00-4.61 mmol/L LDL-C respectively.The following were considered as exclusion criteria;history of cardiovascular disease, cancer or strong familyhistory of cancer, untreated hypertension with bloodpressure >140/90 mmHg, diabetes, hepatic or renaldisease and currently under lipid lowering therapy. Thetrial is registered in clinical trials.gov registry (Identifier:NCT00438425).Study protocolParticipants were recruited by advertisements. The studyprotocol was explained to all participants and signatureson informed consent forms were obtained from eligibleparticipants. Eligible participants were randomized inblocks of 75 participants with stratification by centre,gender and baseline LDL-C concentrations with greaterthan or lesser than 4.09 mmol/L. In this study with aparallel design, participants were randomized to one ofthe three treatment groups with either a therapeutic lowfat diet control or dietary portfolio of cholesterol loweringfoods with either 2 visits (routine) or 7 visits (intensive)during a 6 month period (Figure 1). Participants visitedthe respective centers at baseline and by 3 and 6 monthsfor the control and portfolio routine diet groups. Partic-ipants categorized to intensive dietary portfolio groupvistioRamprasath et al. Nutrition Journal 2014, 13:101 Page 3 of 12http://www.nutritionj.com/content/13/1/101visited the respective centers at baseline, 2 weeks andsubsequently every month. During each of the visits, thepreceding 7-day dietary histories were collected andreviewed along with recording the body weight andblood pressure. Fasting blood samples were collectedfrom the participants during each visit. Serum lipidprofile and apolipoproteins were measured as explainedearlier [4]. This study was conducted according to theguidelines laid down in the Declaration of Helsinki andall procedures were approved by the ethics committeesof Universities of British Columbia, Laval, Manitobaand Toronto as well as St Michael’s Hospital, Toronto.Diets consumed by the participants were previouslyexplained in detail [4]. During the 6 month study treat-ment period, participants received dietary advice bydieticians to follow a weight maintaining vegetarian dietswith foods available at supermarkets and health foodstores. Participants in the dietary portfolio groups wererecommended to incorporate the portfolio dietary studyfoods into their diets. The aim was to provide 0.94 g ofPS in margarine, 9.8 g of viscous fibre, 22.5 g of soyproteins and 22.5 g of nuts per 1000 kcal of diet per day.Control dietary participants were advised to consume lowfat dairy and whole grain cereals along with fruits and vege-tables and to avoid the portfolio dietary components. Allparticipants were supplied with measuring cups and spoonsto control the amount of portfolio and control dietary foodsconsumption. Diets were analyzed using a program basedon US Department of Agriculture data (ESHA Food Pro-cessor SQL version 10.1.1; ESHA, Salem, Oregon).Figure 1 Schematic representation of the study protocol. *Indicatesbody weight and blood pressure measurement and fasting blood collecConcentrations of plasma α and γ tocopherols, β-carotene, lutein, lycopene and retinol were measured con-currently with an isocratic high performance liquid chro-matograph (HPLC) (1100 HPLC, Agilent Technologies,Palo Alto, California) as described earlier [43]. Briefly, in-ternal standards retinol acetate and β-apo-8′-carotenal inmethanol were added to each of the samples and deprotei-nized with ethanol followed by extraction with hexane.Samples were injected into a C18 reverse phase column(Zorbax Eclipse XBD, Agilent Technologies, Palo Alto,California) with a guard column and eluted with mobilephase consisting of methanol, acetonitrile and tetrahydro-furan in the ratio of 75:20:5 (v/v/v). Detection wavelengthswere set at 290, 320 and 450 nm for detection of the com-pounds of interest. Fat-soluble vitamins were identifiedusing authentic standards (Sigma-Aldrich) and were quan-tified using standard curves.Concentrations of PS in plasma were measured bygas chromatography (6890 GC, Agilent Technologies,Palo Alto, California) equipped with a flame ionizationdetector and auto-injector system. A 30-m SAC-5 col-umn (Sigma-Aldrich Canada Ltd., Oakville, Ont.) wasused. Briefly, 5-α cholestane as an internal standardwas added to each of the samples followed by additionof methanolic potassium hydroxide and saponification.Sterols were extracted from the mixture with petrol-eum ether. Extracted samples were derivatized withTMS reagent (pyridine-hexamethyldisilazane-trimethyl-chlorosilane (9:3:1, v/v)) and samples were injectedinto the GC [44]. The injector and detector were setat 300 and 310 degrees C, respectively. The flow rateof the carrier gas, helium was 1.2 ml/min with the in-let splitter set at 100:1. Individual PS were identifiedusing authentic standards (Sigma-Aldrich Canada Ltd.,Oakville, Ont). Internal standards were used to calcu-late detector response factors. Campesterol and β-sitosterol concentrations were determined by identify-ing the peak sizes and expressing them relative to 5-αcholestane internal standard. As PS and fat soluble vi-tamins are mainly transported in cholesterol-containingparticles in serum, the absolute concentrations were ad-justed for the serum cholesterol concentration to elimin-ate the effect of changes in the serum cholesterolit to the centre; collection of 7-day diet record/check lists, satiety score;n.concentration.Statistical analysesData are expressed as means with their standard errors.The significance of the differences between week 0, week12 as well as week 24 between different groups wereassessed by Least Squares Means utilizing PROC MIXEDprocedure in SAS, with Tukey adjustment for multiplicityof comparisons. Analysis of covariance was performedwith sex, treatment, centre and centre-by-treatmentinteraction as main effects and baseline as a covariate. Inall tests of hypotheses, p values <0.05 were consideredsignificant. All statistical analyses were performed usingthe SAS software (version 9.2; SAS Institute Inc., Cary,NC, USA) Sample size determination with LDL-C asprimary end point has been explained in detail earlier [4].ResultsBaseline characteristics of participants and dietary intakesduring the studyBaseline characteristics of participants of all treatmentswere similar except for the relatively higher ratio of mento women on the intensive portfolio group compared tothe other groups (Table 1). Adherence to the dietaryrecommendations assessed from the 7 day food recordsusing food processor software was 46.4% and 40.6% forthe intensive and routine portfolio diets, respectively [4].Dietary macronutrient profile of the portfolio andcontrol diets were explained in Table 2. Participants inintensive and routine portfolio groups consumed 0.8and 0.6 g/d/1000 Kcal PS in their diets, respectively.The amount of vitamin A consumed during the studyby participants in intensive and routine portfoliodietary groups was 1280 and 1248 IU compared withcontrol group which was 1699 IU per day. In contrast,intakes of vitamin E were higher with participants inintensive (3.0 IU/d) and routine (2.8 IU/d) portfoliogroups compared to the control dietary group (1.6 IU/d).Serum lipid profile changes with portfolio and controldietsReductions in serum total and LDL-C level withconsumption of portfolio diets are reported in Table 3[4]. No differences were found between the 3 interven-tion groups in baseline blood lipid concentrations.Percentage change and absolute treatment differencesbetween the control and the two dietary portfoliointerventions were significant for LDL-C (p < 0.001) andin absolute units for the TC:HDL-C ratio (intensive dietaryportfolio: p = 0.004, routine dietary portfolio: p = 0.006),with no significant differences seen between the twodietary portfolio groups (p = 0.66).Effect of portfolio diet on plasma fat soluble compoundconcentrationsPlasma concentrations of tocopherols, carotenoids andretinol and their ratios to cholesterol are shown inTable 4. Participants consuming the intensive portfoliodiet showed no changes in any of the fat soluble vitaminsmeasured except for a slight but significant increase incholesterol adjusted α-tocopherol (p = 0.014) and retinol(p = 0.032) at week 12, but not at week 24. Furthermore,concentrations of β-carotene and retinol were found to bedecreased with intensive portfolio diet only at week 24Ramprasath et al. Nutrition Journal 2014, 13:101 Page 4 of 12http://www.nutritionj.com/content/13/1/101Table 1 Baseline characteristics of participantsCharacteristicPortfolio intensive (n = 101)Age, mean (SD) y 54.6 (9.8)SexMale 50 (49.5%)Female 51 (50.5%)Body weight, mean (SD), kg 75.5 (13.5)Body mass index, mean (SD), kg/m2 26.6 (4.0)Blood pressure, mean (SD), mm HgSystolic 120.9 (12.6)Diastolic 73.1 (9.0)Lipids, mean (SD), mmol/LcTotal 6.53 (1.00)LDL-C 4.42 (0.89)HDL-C 1.42 (0.32)Triglycerides 1.53 (0.73)Medication useLipid lowering medication 13 (12.9%)Antihypertensive medication 18 (17.8%)Hormone-replacement medication 2 (2%)Thyroxine 9 (8.9%)ap-values calculated by ANOVA for continuous variables.bp-values calculated by CHI2/Fisher’s Exact Test for categorical variables.cMean lipid levels for 100 subjects in the portfolio intensive group, for 122 subjectsTreatments P-valuea, bPortfolio routine (n = 122) Control (n = 122)57.1 (8.3) 56.9 (9.3) 0.08237 (30.3%) 47 (38.5%) 0.01485 (69.7%) 75 (61.5%)73.7 (13.3) 76.9 (13.8) 0.18926.9 (3.8) 27.4 (3.9) 0.244119.5 (13.5) 119.9 (11.9) 0.68373.8 (8.3) 73.0 (8.0) 0.7316.63 (1.06) 6.45 (0.87) 0.8304.50 (0.88) 4.35 (0.72) 0.3801.40 (0.40) 1.39 (0.36) 0.8361.61 (0.83) 1.65 (0.98) 0.57420 (16.4%) 18 (14.8%) 0.75417 (13.9%) 28 (23.0%) 0.1937 (5.7%) 2 (1.6%) 0.19511 (9%) 15 (12.3%) 0.627in the portfolio routine, and for 121 subjects in the control.robasRamprasath et al. Nutrition Journal 2014, 13:101 Page 5 of 12http://www.nutritionj.com/content/13/1/101(β-carotene: p = 0.017; retinol: p = 0.007). No significantchanges in any fat soluble vitamin concentrations werenoted in routine portfolio diet group, except for anincrease in cholesterol adjusted γ-tocopherol at week 12(p = 0.003), as well as at week 24 (p = 0.014) anddecreased β-carotene (p = 0.016) and α-tocopherol(p = 0.041) only at week 12, but not at week 24. Con-sumption of the control diet had no impact on plasmavitamin concentrations except for an increase in chol-esterol adjusted β-carotene at week 12 (p = 0.018) butnot at week 24.No differences between the three dietary interven-tions were observed with changes from respective base-lines of any of fat soluble vitamins measured except fora significant reduction in concentration of β-carotene atweek 12 with intensive (p = 0.045) and routine (p = 0.031)portfolio diet, compared to changes with control diet. How-ever, the change from baseline in β-carotene concentrationTable 2 Macronutrient intake profiles of portfolio and contNutrients Portfolio intensive(n = 101)Energy, Kcal/d 1977Total protein 88(18)Available carbohydrate 225(45)Total dietary fibre (g/100 kcal) 42(22)Total fat 70(32)Saturated fatty acid 14(7)Monounsaturated fatty acid 27(12)Polyunsaturated fatty acid 18(9)Cholesterol (mg/1000 kcal) 123(66)Data are expressed as mean grams per day (% energy intake) unless stated andat week 24 with routine portfolio diet group was notdifferent (p = 0.078) when compared to change withcontrol diet group, but was lower with >intensive port-folio diet (p = 0.039) compared to changes from base-lines observed in control dietary group. Furthermore,cholesterol adjusted concentrations of fat soluble vita-mins, especially β-carotene, were not different acrossintervention groups. Changes in cholesterol adjustedconcentrations of plasma fat soluble compounds withportfolio diet consumption were negatively correlated withchanges in total cholesterol (α-tocopherol: p = 0.005;retinol: p = 0.008; lutein: p = 0.031; lycopene: p = 0.004; β-carotene: p = 0.009) and LDL-C (α-tocopherol: p = 0.004;retinol: p = 0.004; lutein: p = 0.027; lycopene: p = 0.004;β-carotene: p = 0.013) levels (Table 5). Furthermore,changes in cholesterol adjusted plasma concentrationsof α-tocopherol (p = 0.026), retinol (p = 0.038) and lycopene(p = 0.048) showed a negative correlation with serum apoBconcentrations.Changes in plasma plant sterol concentrations during thestudyPlasma PS concentrations including campesterol andβ-sitosterol and their ratio with cholesterol are depictedin Figure 2. The intensive portfolio diet group showedan increase in concentration of campesterol at week 24(p = 0.034) compared with baseline. Similarly, partici-pants consuming the routine portfolio dietary groupalso demonstrated increased campesterol concentra-tions at both weeks 12 (p < 0.001) and 24 (p < 0.001),respectively, compared to baseline. Ratios of campes-terol and cholesterol were also found to be increasedby intensive (p = 0.001 at week 12, p < 0.001at week 24)as well as routine (p < 0.001 at week 12 and 24) portfoliodiet consumption. No significant changes in campesteroland cholesterol-adjusted campesterol concentrations wereobserved after consuming the control diet. Plasma con-centrations of β-sitosterol were found to be increased inl diets during the studyPortfolio routine(n = 122)Control(n = 122)1804 180279(18) 80(18)208(46) 225(50)36(20) 31(17)63(31) 52(26)14(7) 14(7)24(12) 19(9)16(8) 11(6)120(68) 154(86)ed on the dietary data obtained at week 24 of the study.both intensive (p = 0.008 at week 12, p < 0.001 at week 24)and routine (p < 0.001 at week 12 and 24) portfolio dietgroups. Increases in cholesterol adjusted β-sitosterolconcentrations in plasma were similarly elevated asunadjusted β-sitosterol concentrations (p < 0.001) atweek 12 and 24 after intensive or routine portfolio dietconsumptions compared to their baselines. Concentra-tions of β-sitosterol and its ratio to cholesterol weresignificantly elevated in participants consuming controldiet at 12 weeks (β-sitosterol: p = 0.024; ratio to choles-terol p = 0.032) as well as at 24 weeks (p = 0.05).No differences across time were observed across par-ticipants consuming intensive and routine portfoliodiet in circulating campesterol and β-sitosterol levels,or their ratios to cholesterol. However, increased plasmacampesterol and β-sitosterol concentrations were ob-served with both intensive (week 24: p = 0.012 for campes-terol and p = 0.035 for β-sitosterol) as well as routine(week 24: p = 0.034 for campesterol and p = 0.080 for β-Table 3 Effect of portfolio and control diets on blood lipids levels and the differences between dietary interventionsTreatmentsa Between treatment differencesbVariable Portfolio intensive (n = 101) Portfolio routine (n = 122) Control (n = 122) PI vs. PR PI vs. C PR vs. CWk 0 Wk 24 Wk 0 Wk 24 Wk 0 Wk 24 Mean (95% CI) P-value Mean (95% CI) P-value Mean (95% CI) P-valueCholesterol, mmol/LTotal 6.53 5.88 6.63 6.04 6.46 6.41 −0.07 (−0.31, 0.17) 0.777 −0.56 (−0.80, −0.33) <0.0001 −0.49 (−0.73, −0.26) <0.0001LDL-C 4.42 3.80 4.50 3.92 4.35 4.24 −0.06 (−0.27, 0.15) 0.773 −0.46 (−0.67, −0.26) <0.0001 −0.40 (−0.60, −0.20) <0.0001HDL-C 1.42 1.39 1.40 1.39 1.39 1.40 0.007 (−0.006, 0.072) 0.965 −0.02 (−0.09, 0.04) 0.619 −0.03 (−0.09, 0.03) 0.453Triglycerides 1.52 1.50 1.61 1.60 1.66 1.72 −0.06 (−0.23, 0.12) 0.743 −0.10 (−0.27, 0.07) 0.372 −0.04 (−0.21, 0.13) 0.824Total:HDL-C 4.81 4.44 5.01 4.60 4.93 4.87 −0.05 (−0.27, 0.17) 0.852 −0.33 (−0.54, −0.11) 0.001 −0.28 (−0.50, −0.06) 0.008Apolipoproteins g/LA1 1.60 1.60 1.60 1.60 1.60 1.59 0.02 (−0.02, 0.06) 0.533 0.01 (−0.03, 0.05) 0.868 −0.01 (−0.05, 0.03) 0.819B 1.23 1.10 1.26 1.14 1.20 1.20 −0.01 (−0.06, 0.03) 0.846 −0.11 (−0.16, −0.07) <0.0001 −0.10 (−0.15, −0.06) <0.0001aFor paired samples T-test of change from baseline, done on absolute change values.bUsing analysis of covariance with sex, treatment and sex by treatment interaction as main effects and baseline as a covariate. A Tukey adjustment was made for multiple comparisons. Abbreviations: PI Portfoliointensive, PR Portfolio routine, C Control.Ramprasathetal.NutritionJournal2014,13:101Page6of12http://www.nutritionj.com/content/13/1/101Table 4 Plasma concentrations of carotenoids, tocopherols and retinoids following portfolio and control dietsVariable Intensive portfolio Routine portfolio ControlWk 0 Wk 12a Wk 24a Wk 0 Wk 12a Wk 24a Wk 0 Wk 12a Wk 24aMean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEMα-tocopherolb 47.72 2.51 45.60 2.71 45.23* 2.55 50.15 2.37 47.36* 2.77 47.50 2.83 51.05 2.71 51.76 2.99 49.72 3.05γ-tocopherolb 4.97 0.22 4.76 0.29 4.71 0.29 5.28 0.30 5.10 0.35 4.99 0.36 4.96 0.30 5.22 0.37 5.21 0.35Lycopeneb 2.61 0.13 2.49 0.23 2.49 0.13 2.78 0.20 2.53 0.17 2.56 0.17 3.21 0.20 3.23 0.17 3.06 0.23Luteinb 1.65 0.19 1.51 0.21 1.64 0.21 1.80 0.17 1.67 0.16 1.80 0.18 1.71 0.15 1.77 0.18 1.69 0.19β-caroteneb 2.24 0.19 2.07† 0.18 2.06*† 0.19 2.27 0.17 2.11*† 0.17 2.20† 0.17 2.23 0.18 2.38 0.18 2.45 0.17Retinolb 2.78 0.12 2.65 0.16 2.65* 0.15 2.94 0.15 2.88 0.13 2.83 0.15 2.73 0.12 2.86 0.15 2.84 0.19α-tocopherol:TCc 7.46 0.46 8.39* 0.51 8.00 0.49 7.91 0.46 8.41 0.55 8.25 0.49 8.07 0.53 8.54 0.53 8.04 et al. Nutrition Journal 2014, 13:101 Page 7 of 12http://www.nutritionj.com/content/13/1/101sitosterol) portfolio diet groups, compared with controldiet. Plasma campesterol and β-sitosterol concentrationsafter adjusting for blood cholesterol concentrations werealso found to be elevated after consumption of intensive(week 12: p = 0.037 for campesterol:TC and p = 0.022 forβ-sitosterol:TC; week 24: p = 0.001 for campesterol:TCand p = 0.002 for β-sitosterol:TC) and routine (week 12:p = 0.054 for β-sitosterol:TC; week 24: p = 0.003 for cam-γ-tocopherol:TCc 0.79 0.04 0.88 0.05 0.81 0.05 0.80 0Lycopene:TCc 0.42 0.02 0.45 0.04 0.44 0.02 0.42 0Lutein:TCc 0.29 0.04 0.29 0.04 0.30 0.04 0.29 0β-carotene:TCc 0.35 0.04 0.38 0.03 0.37 0.04 0.36 0Retinol:TCc 0.43 0.02 0.49* 0.03 0.47 0.03 0.47 0*Indicates significance compared to respective baseline. †indicates significance waUsing analysis of covariance with sex, treatment and sex by treatment interactiomultiple comparisons. bμmol/L. cμmol/L:mmol/L.pesterol:TC and p = 0.002 for β-sitosterol:TC) portfoliodiets, compared with consumption of the control diet.Changes in plasma campesterol:TC ratio with portfoliodiet were found to be negatively correlated with total(p = 0.0001) and LDL-C (p = 0.0004), as well as withapoA1 (p = 0.001) and ApoB (p = 0.002) levels and LDL-C/ApoB ratio (p = 0.009) (Table 6). Similarly, changes inplasma β-sitosterol:TC ratios after consuming portfoliodiets were also observed to be negatively correlated withTable 5 Correlations between changes in plasma carotenoid,markers after consumption of portfolioVariable γ-tocopherol:TC α-tocopherol:TCTC N 161 161r −0.111 −0.219P 0.161 0.005LDL-C N 160 160r −0.088 −0.225P 0.271 0.004ApoB N 161 161r −0.073 −0.175P 0.360 0.026the change in total (p = 0.0002) and LDL-C (p = 0.0001) andApoB (p = 0.0004) levels, as well as in cholesterol:HDL-Cratio (p = 0.021), LDL-C:HDL-C ratio (p = 0.010), apoB:apoA1 ratio (p = 0.001) and LDL-C:apoB ratio (p = 0.036).DiscussionResults demonstrate that intake of a portfolio diet for6 months improved blood lipid concentrations without0.91* 0.07 0.88* 0.07 0.81 0.06 0.86 0.06 0.83 0.050.44 0.03 0.45 0.03 0.50 0.04 0.54 0.03 0.49 0.040.31 0.03 0.32 0.03 0.28 0.03 0.29 0.03 0.28 0.030.38 0.03 0.38 0.03 0.35 0.03 0.40* 0.03 0.39 0.030.52 0.03 0.50 0.03 0.43 0.02 0.47 0.03 0.46 0.03changes from baseline compared to control at respective time point.as main effects and baseline as a covariate. A Tukey adjustment was made foraltering the plasma fat soluble vitamin concentrationsafter adjustment for cholesterol levels. Phytosterol intakehas been believed to result in a possible reduction inabsorption of fat soluble vitamins which in turn mightlead to their lower levels in plasma [33,34,37]. Caroten-oids, retinols and tocopherols are absorbed in the intestinein a similar fashion to lipids. PS lower blood cholesterol byinhibiting cholesterol absorption in the gut. Hence, thepossibility exists that consumption of PS might reducetocopherol and retinoid concentrations with lipidRetinol:TC Lutein:TC Lycopene:TC β-carotene:TC161 159 157 156−0.209 −0.171 −0.230 −0.2090.008 0.031 0.004 0.009160 158 156 155−0.228 −0.176 −0.229 −0.2000.004 0.027 0.004 0.013161 159 157 156−0.163 −0.138 −0.158 −0.1290.038 0.083 0.048 0.110thesbinatmRamprasath et al. Nutrition Journal 2014, 13:101 Page 8 of 12http://www.nutritionj.com/content/13/1/101Figure 2 Plasma concentrations of plant sterols and their ratios wiCampesterol, b. β-sitosterol, c. campesterol:TC, d. β-sitosterol:TC. *Indicatwith changes from baseline compared to control at respective time point.portfolio at respective time point. Using analysis of covariance with sex, trecirculating concentrations of these fat soluble com-pounds due to their reduced intestinal absorption [27].Reductions in serum carotenoids and lycopene con-centrations in normocholesterolemic and mildly hyper-cholesterolemic participants were observed with PSconsumption [27,35,36,45,46]. Reductions in plasmafat soluble compounds concentrations found in theseinterventions might be because of their lower absorp-tion or due to reduced lipoprotein carriers and serumcholesterol concentrations. However, when concentra-tions of these fat soluble compounds were correctedfor plasma lipid levels, only carotene concentrationswere shown to be reduced in some trials [27,35]. In thecurrent intervention, no such reductions occurred inany of the measured plasma fat soluble compoundlevels across intervention groups suggesting that othercomponents of the portfolio diet might have compensatedfor the effect of PS on fat soluble vitamins. Vitamins Aand E are essential to maintain normal health and immunesystem and their deficiency lead to chronic diseases[28,31]. Consumption of portfolio diet did not affect theplasma concentration of these vitamins which indicatesthe safety with the portfolio diet with absorption of fatsoluble compounds.Results from current intervention showed no changesacross the three dietary groups in plasma concentrationsof tocopherols, retinoids and carotenoids, except for acovariate. A Tukey adjustment was made for multiple comparisons.cholesterol after consumption of portfolio and control diets. a.significance compared to respective baseline. †indicates significancedicates significance with changes from baseline compared to routineent and sex by treatment interaction as main effects and baseline as adecrease in β-carotene with portfolio groups comparedto the control diet group. However, the cholesteroladjusted β-carotene concentrations in plasma showed nodifferences across all the groups. These findings indicatethat consumption of a portfolio diet reduces blood chol-esterol but does not affect the absorption of fat solublevitamins. No changes in cholesterol adjusted fat solublevitamins concentrations with portfolio diet consumptionalso indicate that decreased plasma carotenoid concen-trations reflect reductions in carrier lipoproteins,especially LDL-C. Results of earlier studies are variableranging from no change in any of the fat soluble com-pounds in serum [39,41,47,48] to considerable changes[38] or differences only in β-carotene [49-51]. The lackof consistency in results might be due to differentbackground diets during the intervention and eatinghabits of the participants. In most of the interventions,diets are not strictly controlled and supervised bystudy investigators. In contrast, well-controlled humantrials with strictly controlled diets have shown nosignificant differences in concentrations of circulatingfat soluble compounds [40,48].In the current trial, participants in intensive androutine portfolio diet groups consumed significantlyhigher amounts of vitamin E compared to participantsconsuming the control diet, which might also be areason for not finding any reduction in plasma vitamin ERamprasath et al. Nutrition Journal 2014, 13:101 Page 9 of 12http://www.nutritionj.com/content/13/1/101Table 6 Correlations between changes in plasma plantsterol concentrations and lipid markers with portfoliodiet consumptionVariable Campesterol:TC β-sitosterol:TCTC N 156 152R −0.302 −0.294P 0.0001 0.0002LDL-C N 155 151R −0.281 −0.307P 0.0004 0.0001ApoA1 N 156 152R −0.269 −0.019P 0.001 0.815ApoB N 156 152R −0.242 −0.285P 0.002 0.0004concentrations after consuming portfolio diet. Theamount of vitamin A consumption was not signifi-cantly different with portfolio dietary groups comparedto respective baselines. However, dietary intake ofvitamin A by participants in control group was signifi-cantly higher than that of the portfolio group whichcould have contributed to the increase observed inplasma vitamin A concentrations after the control dietintake, compared with the portfolio dietary groups.Several investigators recommended consumption ofcarotenoid rich foods including fruits and vegetablesalong with PS consumption to prevent reductions infat soluble compound levels [12,51,52]. PS did notaffect the β-carotene absorption in participants withmild hypercholesterolemia when consumed PS esteri-fied to fish oil, but not to sunflower oil [47]. Earlierstudies have also shown that PS consumption whendistributed over the day results in an optimal choles-terol lowering effect rather than a single large dose[6,53]. Hence, the background diet and feeding strategyTC/HDL-C N 155 151R −0.008 −0.188P 0.921 0.021LDL-C/HDL-C N 155 151R −0.046 −0.209P 0.568 0.010ApoB/ApoA1 N 156 152R −0.056 −0.265P 0.488 0.001LDL-C/ApoB N 154 150R −0.211 −0.172P 0.009 0.036play important roles in terms of effects of PS consumptionon plasma concentrations of fat soluble compounds.Plasma concentrations of retinol and tocopherols wereconsistent with the ranges seen in our previous publica-tions [47,48,54] as well as Sowell et al. [55]. Althoughthe plasma carotenoid concentrations in the currentstudy appear to be slightly higher than values observedby other researchers [55], they were in the same rangeas found earlier [48]. Plasma samples could be detectedwith not only the compounds of interest for measure-ment in the study but also other compounds such asalpha-cryptoxanthin, cis-beta-carotene (13-cis), cislyco-pene (at least three isomers), cis-lutein/zeaxanthin etc.Presence of the compounds might lead to detection ofhigher concentration of a given compound which alsodepends on the relative concentrations of the analyte aswell as the interferent. Olmedilla et al. measured theplasma retinol, tocopherol and carotenoid concentra-tions in the Spanish population and compared theirconcentrations with those of other country’s populations[56]. Results indicated that carotenoid concentrationsshowed differences from two to five fold in the reportedvalues. Variations might be due to differences betweenpopulation and seasonality.Consumption of our PS containing diet resulted insubstantial increases in plasma concentrations of bothcampesterol and β-sitosterol. Previous trials with humanshave shown that consumption of 1.8 g/day of PS increasesplasma campesterol and β-sitosterol concentrations from9 to 16.6 and 4.4 to 6.0 μmol/ L respectively [57]. Resultsfrom current work were consistent with the previous datawhere consumption of portfolio diet consisting 2 g/dof PS increased the plasma PS concentrations [58].Supplementation of a larger dose of 6.6 g/day of PS ledto elevations in circulating campesterol and β-sitosterolconcentrations from 7.8 to 15.8 and 8.0 to 11.4 μmol/Lrespectively [49]. In those trials, plasma PS concentrationswere considerably lower than those seen in homozygousphytosterolemic patients who presented with levels of290–966 μmol/L [17,59].Some studies have suggested that moderately increasedconcentrations of PS in plasma could be associated withincreased risk of CVD [13,14]. Glueck et al. and Assmannet al. observed correlations between campesterol orβ-sitosterol alone and CVD risk, respectively [13,14].However, these trials concluded that an associationexists between plasma PS concentrations and CVDrisk, but failed to find the correlations with CVD riskindependently from plasma cholesterol concentrationswhich itself is a risk factor for CVD. A number ofinvestigations with different study designs have shownthat plasma PS levels have no association with the riskof CVD [20-22,60-62]. Results of the current investiga-tion showed significant negative correlations betweenRamprasath et al. Nutrition Journal 2014, 13:101 Page 10 of 12http://www.nutritionj.com/content/13/1/101plasma PS concentrations and total and LDL-C, as wellas apoB. However, no significant correlation was foundbetween the Framingham risk score and plasma PSconcentrations in the present work. In a trial with 2542middle aged humans, plasma PS concentrations failedto be associated with increased risk of CVD [21]. Simi-larly, the prospective EPIC-Norfolk population studyhad failed to observe any differences in PS concentra-tions in plasma of healthy participants who developedCVD during the 6 year follow up when compared totheir case matched controls [20]. In the LongitudinalAging Study Amsterdam (LASA), with 1242 partici-pants with 65 years of age, moderately increased con-centrations of plasma PS were shown to be associatedwith reduced CVD risk [19]. Based on these findings,increased plasma PS concentrations due to consump-tion of PS cannot be considered to be associated withelevated CVD risk. It can be ventured that finite meritexists in maintaining circulating PS levels in the upperrange of normal to minimize disease risk.The study has some limitations as follows. Intake ofvitamin E levels during the study was higher with portfo-lio diet compared with control. In addition, vitamin Aintake was higher with control compared to the twoportfolio diet groups. Due to the complex nature of thedietary intervention, the vitamin intakes were not sameacross all the groups. Portfolio diet consisted of combin-ation of various food components and hence thechanges in lipids, sterols and vitamins cannot be attrib-uted to one single component. The study was a freeliving study and not metabolically well controlled byproviding all the foods to the participants and followmore closer. Hence, the compliance during the studywas less than 50% and drop out rate was 22.6%. How-ever, the aim of the study was to determine the effect ofthe portfolio diet in real world conditions without muchmetabolic control and so the drop out rates is asexpected. Health benefits could be more than found inthe study if the diet is followed more strictly.In conclusion, consumption of a portfolio diet includingPS, viscous fibres, soy proteins and nuts for 6 monthsreduced blood cholesterol levels without affecting fat solublevitamin levels. Consequently, the portfolio diet consumptionnot only reduces serum LDL-C, but also counteracts effectsof PS in reducing plasma fat soluble vitamins. Hence,consuming portfolio diet could be considered as one ofthe best options to maintain normal blood lipid levelsand reduce risk of CVD without any adverse effects.AbbreviationsCVD: Cardiovascular disease; HDL-C: High density lipoprotein cholesterol;LDL-C: Low density lipoprotein cholesterol; PS: Plant sterols.Competing interestsDr. Ramprasath reported receiving grants from CRCE of the FederalGovernment of Canada, CIHR, AFM Net, Loblaw Brands Ltd, Solae, andUnilever. Dr. Jenkins reported serving on the Scientific Advisory Board ofUnilever, Sanitarium Company, California Strawberry Commission, LoblawSupermarket, Herbal Life International, Nutritional Fundamental for Health,Pacific Health Laboratories, Metagenics, Bayer Consumer Care, Orafti, DeanFoods, Kellogg’s, Quaker Oats, Procter & Gamble, Coca-Cola, NuVal GriffinHospital, Abbott, Pulse Canada, Saskatchewan Pulse Growers, and CanolaCouncil of Canada; receiving honoraria for scientific advice from the AlmondBoard of California, International Tree Nut Council Nutrition Research andEducation Foundation, Barilla, Unilever Canada, Solae, Oldways, Kellogg’s,Quaker Oats, Procter & Gamble, Coca-Cola, NuVal Griffin Hospital, Abbott,Canola Council of Canada, Dean Foods, California Strawberry Commission,Haine Celestial, and Alpro Foundation; being on the speakers panel for theAlmond Board of California; receiving research grants from Loblaw BrandsLtd, Unilever, Barilla, Almond Board of California, Solae, Haine Celestial,Sanitarium Company, Orafti, International Tree Nut Council, and PeanutInstitute; and receiving travel support to meetings from the Almond Boardof California, Unilever, Alpro Foundation, and International Tree Nut Council.Dr. Jenkins’ wife is a director of Glycemic Index Laboratories, Toronto,Ontario, Canada, and his sister, Caroline Brydson, contributed to the dietbooklet used in the study, which may in the future be expanded to bookform for the general public. Dr. Jones reported receiving grants from theCanadian Institutes of Health Research (CIHR), Canada Research ChairEndowment (CRCE) of the Federal Government of Canada, Advanced Foodsand Materials Network (AFM Net), Danone, Enzymotec, and Unilever. Dr. Jonesalso serves as president of Nutritional Fundamentals for Health Inc, whichmarkets plant sterols among other nutraceuticals. Dr. Lamarche reportedreceiving grants from CIHR and AFM Net, being a consultant and on speakersbureaus for Danone, and receiving royalties from Atrium Innovations. Dr.Kendall reported being on speakers bureaus for Almond Board of California,Solae, and Unilever; and receiving research grants from CIHR, Unilever,Solae, Loblaw Brands Ltd, International Tree Nut Council, and AlmondBoard of California. Dr. Faulkner reported receiving grants from CRCE of theFederal Government of Canada, CIHR, AFM Net, Loblaw Brands Ltd,Unilever, and Solae. Ms. Cermakova reported receiving grants from CRCE ofthe Federal Government of Canada, CIHR, AFM Net, Loblaw Brands Ltd,Unilever, Solae, and Viterra Food Processing-Oat and Specialty Grain Milling.Dr. de Souza reported receiving grants from Coca-Cola, Calorie ControlCouncil, and CIHR. Mr. Ireland reported receiving grants from CRCE of theFederal Government of Canada, CIHR, AFM Net, Loblaw Brands Ltd, Solae, andUnilever. Ms. Patel reported receiving grants from CRCE of the FederalGovernment of Canada, CIHR, AFM Net, Loblaw Brands Ltd, Solae, and Unilever.Dr Bashyam reported receiving grants from CIHR, CRCE of the FederalGovernment of Canada, AFM Net, Loblaw Brands Ltd, Solae, and Unilever.No other authors reported any conflict of interest.Authors’ contributionsVRR contributed in conducting the study, data acquisition, laboratoryanalyses, and data interpretation and wrote the manuscript. DJ, BL, CK, DF,PC, PWC, JF and PJHJ designed and monitored the study, were involved indata analysis and revision of the manuscript. LC, CI, SA, DP, BB, KS, RGJ andLAL were involved in conducting the study, data acquisition. RDS and EVwere involved in data analysis and interpretation. All the authors contributedto revisions of the manuscript and reviewed the final version.AcknowledgementsThe authors would like to acknowledge the work done by Dr. Aparna Kuna,Assistant Professor, Acharya N G Ranga Agricultural University, Hyderabad,India with sample preparation and analysis of plant sterols at the RCFFN.Funding/SupportThis work was supported by the CRCE of the Federal Government of Canada(Drs Jenkins, Jones, and Lamarche), CIHR, AFM Net, Loblaw Brands Ltd, Solae(St Louis, Missouri), and Unilever (Vlaardingen, the Netherlands, and Toronto,Ontario, Canada). Dr. Jenkins receives salary support as a Canada ResearchChair from the federal government of Canada. Unilever Research andDevelopment provided the donation of margarines used in the study andCan-Oat Milling, a division of Viterra Inc (Portage La Prairie, Manitoba,Canada), provided the generous donation of HiFi medium oat bran used forthe study breads and funding for freezer acquisition. St Michael’s HospitalFoundation provided funding for the production of the study booklet.Ramprasath et al. Nutrition Journal 2014, 13:101 Page 11 of 12http://www.nutritionj.com/content/13/1/101Author details1Richardson Centre for Functional Foods and Nutraceuticals, Winnipeg, MBR3T 2 N2, Canada. 2Department of Human Nutritional Sciences, University ofManitoba, Winnipeg, MB, Canada. 3Clinical Nutrition & Risk FactorModification Center, Toronto, ON, Canada. 4Department of Medicine, Divisionof Endocrinology and Metabolism, St. Michael’s Hospital, Toronto, ON,Canada. 5Departments of Nutritional Sciences, University of Toronto, Toronto,ON, Canada. 6Faculty of Medicine, University of Toronto, Toronto, ON,Canada. 7Institute of Nutrition and Functional Foods, Laval University,Quebec City, Quebec. 8Department of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, British Columbia. 9Institute ofMedical Science, Faculty of Medicine, University of Toronto, Toronto, ON,Canada. 10Department of Clinical Epidemiology & Biostatistics, McMasterUniversity, Hamilton, ON, Canada. 11Keenan Research Centre of the Li KaShing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada.Received: 10 June 2014 Accepted: 7 October 2014Published: 18 October 2014References1. 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