Lathosterol in plasma measures cholesterol synthesis and identifies the efficiency of dietary phytosterols in reducing the plasma cholesterol concentration

Lathosterol in plasma measures cholesterol synthesis and identifies the efficiency of dietary phytosterols in reducing the plasma cholesterol concentration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Lathosterol in plasma measures cholesterol synthesis and identifies the efficiency of dietary phytosterols in reducing the plasma cholesterol concentration Valeria Sutti Nunes, Angela Oliveira Godoy Ilha, Guilherme Silva Ferreira, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-26174/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Because the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol measured by the gold standard isotopic procedure we investigated whether the intestinal absorption of phytosterols (PS) depends on the body's cholesterol synthesis rate. Methods 38 volunteers (58 ± 12 years; low-density lipoprotein cholesterol (LDL-C) ≥ 130 mg/dL) were randomly assigned to consume 400 mL/day of soy milk or soy milk + PS (1.6 g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and markers of phytosterol (PS) absorption and non-cholesterol sterol synthesis precursors measured. Results PS treatment reduced plasma total cholesterol concentration (-5,5%, p < 0.001), LDL-C (-7.6%, p < 0.001), triglycerides (-13.6%, p < 0.0085), and apolipoprotein B (apo B) (-6.3%, p < 0.008), without changing high density lipoprotein cholesterol (HDL-C concentration). The lathosterol-to-cholesterol ratio in serum predicted the serum cholesterol response to PS feeding where high basal cholesterol synthesis was associated with lack of response of plasma cholesterol to PS in the diet. Cholesterol synthesis being elevated in the placebo phase in non-responders to dietary PS indicated they were resistant to further synthesis rise, whereas responders, because they have lower synthesis rate than non-responders in the placebo phase, are capable expanding synthesis under the effect of alimentary PS. Conclusions responders absorbed more PS than non-responders likely resulting from responders delivering less endogenous cholesterol than non-responders into the intestinal lumen that facilitates greater absorption of PS by the intestine. Cardiac & Cardiovascular Systems Endocrinology & Metabolism cholesterol lathosterol phytosterols diet Introduction It is well known that phytosterols (PS) reduce plasma total cholesterol and low-density lipoproteins cholesterol (LDL-C) [ 1 ] [ 2 ] [ 3 ] due to displacement of cholesterol from the intestinal lumen micelles [ 4 ] [ 5 ] and for exerting their molecular actions inside enterocytes and hepatocytes [ 6 ]. Moreover, it was also demonstrated that PS could induce LDL receptor expression [ 7 ]. Because of the beneficial effects on lipid profile, the 2001 National Cholesterol Education Program (NCEP ATP-III) (National Cholesterol Education Program Expert Panel) included PS in the dietary treatment for moderate hypercholesterolemia [ 8 ]. However, after the publication of this guideline, some reports have shown that high PS plasma and tissue concentrations related to increase on cardiovascular risk [ 9 ] [ 10 ]. Nevertheless, Bombo et al. [ 11 ]clearly showed that LDL receptor knockout mice fed a high saturated fat diet supplemented with 2 g of PS did not accumulate sterols on aortic valve or arterial wall. On the other hand, PS treatment prevented atherosclerotic lesion development in hypercholesterolemic mice models [ 11 ]. Plasma concentrations of PS, and of non-cholesterol sterol precursors of cholesterol synthesis, respectively, markers of the intestinal cholesterol absorption and of the body’s cholesterol synthesis have been utilized as markers of atherosclerotic cardiovascular disease [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ]. Nonetheless, objections of diverse nature have been raised on the interpretation of the results utilizing plasma PS measurements as markers of intestinal cholesterol absorption and non-cholesterol precursors as markers of cholesterol synthesis. In this regard, high plasma PS were reported inappropriate cholesterol absorption surrogates because PS in the diet lowered the intestinal cholesterol absorption rate [ 18 ]. Furthermore, in an investigation on moderate hypercholesterolemia, the plasma campesterol/cholesterol ratio did not differ between groups that absorb different amounts of cholesterol measured by the gold standard isotopic procedure [ 19 ]. Therefore, elevation of plasma PS may represent defect in the body's efficiency to re-excrete PS and not an increase in the intestinal absorption of dietary cholesterol. In this regard it is important to take into account that the biliary excretion of plasma PS was more efficient than of plasma cholesterol [ 20 ]. Retention of PS in plasma and other tissues may not be due to their increased absorption by intestinal mucosal cells. Consequently, it is questionable whether increased intestinal uptake of PS relates to premature atherosclerosis in humans. Accordingly, cardiovascular disease (CVD) mortality related reciprocally with PS (sitosterol) as a cholesterol absorption marker: the high desmosterol/sitosterol ratio suggested high cholesterol synthesis and low absorption associated with high total and CVD mortality [ 21 ]. Nonetheless, low serum lathosterol, but not absorption markers, had also been associated with increased CVD [ 17 ]. In contrast, as expected, increased excretion of endogenous cholesterol, which represents increased synthesis, was negatively associated with carotid intima-media thickness [ 22 ]. Consequently, the validity of the role on cardiovascular risk of the serum sterol synthesis and absorption markers remains questionable. In one study in children dietary PS altered the PS concentration in serum but not the concentrations of cholesterol synthesis precursors [ 23 ]. Contrarily, in one study on low cholesterol synthesis cases during the placebo period it was shown that high intestinal sitosterol absorption occurred on PS feeding [ 24 ] but the latter was not mentioned in the other study [ 25 ]. To investigate these previous discrepancies, we measured in plasma the concentrations of precursors of cholesterol synthesis and PS as markers of intestinal absorption of cholesterol in the placebo phase and after ingestion of PS. Methods Subject recruitment The individuals (n = 38: female 31 and male 7) aged 38–77 years were recruited in the Dyslipidemia Outpatient Unit of the Endocrinology and Metabolism Service of the Clinical Hospital of the University of Sao Paulo, Brazil; members of the staff of the University of Sao Paulo, Brazil were also included. The participants were invited for screening of body weight and height; blood samples were collected for lipids profile determination. The inclusion criteria were: body mass index (BMI) between 20 and 30 kg/m 2 ; total cholesterol between 200–300 mg/dL, LDL-C concentrations ≥ 130 mg/dL, and triglycerides ≤ 250 mg/dL (Table 1 ). Exclusion criteria were: use of lipid-lowering medication or a prescribed diet in the last month; alcohol abuse or illicit drug users; pregnancy or breast feeding; smoking; diabetes mellitus, hypothyroidism, renal or hepatic diseases or participation in another lifestyle or pharmaceutical intervention studies. All subjects provided informed written consent. The Ethics in Research Committee of the Hospital of the University of Sao Paulo Medical School approved the study protocol (CAPPesq n° 112/06). Table 1 Subjects characteristics at baseline Parameter Mean ± SD n 38 Age (years) 58 ± 12 Weight (Kg) 64 ± 10 BMI (kg/m 2 ) 25.3 ± 2.4 Total cholesterol (mg/dL) 245 ± 34 Triglycerides (mg/dL) 141 ± 53 LDL-C (mg/dL) 165 ± 34 HDL-C (mg/dL) 49 ± 12 BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol Study Design The present study was a randomized, double-blind, placebo-controlled dietary intervention trial with each study period lasting 4 weeks. Initially, all the participants were submitted to a 3-week run-in period in which they received the placebo product (soy milk) to test adherence to the protocol. After baseline period the individuals were randomly assigned to placebo or to phytosterol groups for 4 weeks; after that a reverse sequence was immediately carried out. Placebo group received 400 mL of soy milk daily; phytosterol group received 400 mL of soy milk enriched with 1.6 g of PS, as follow: 78% β-sitosterol-ester, 13% sitostanol-ester, 5.3% campesterol-ester and 0.5% campestanol-ester (Table 2 ). Blood samples were drawn for biochemical analysis from fasting participants on the last day of each period study. All participants were advised to maintain body weight and follow a normocaloric diet based on the NCEP-ATPIII recommendation [ 8 ]: 30% of energy as fat, < 10% of energy as saturated fat, and < 300 mg cholesterol/day and was recommended not to consume products enriched with phytosterol during the study. Nutritional monitoring was carried out by a registered dietitian using a 24-hour dietary recall to ensure adherence to the prescribed diet and also to estimate the food intake. Soy milk was weekly supplied at the same day of the body weight measurement; patients were instructed to consume the soy milk or PS-enriched soy milk twice daily, at lunch and dinner. Table 2 Soy milk nutritional composition per portion (200 mL)*. Nutritional composition Soy milk Soy milk + PS Energy (kcal) 138 144 Protein (g) 6.5 6.5 Total fat (g) 4.4 5.0 Polyunsaturated fat 2.3 2.5 Monounsaturated fat 1.0 1.1 Saturated fat 0.7 0.9 Trans fatty acid 0 0 Cholesterol (mg) 0 0 Carbohydrates (g) 18.2 18.2 Total sugar 14.1 14.1 Lactose 0 0 Phytosterol (g) 0 0.8 β-sitosterol-ester 0.63 Sitostanol-ester 0.10 Campesterol-ester 0.05 Campestanol-ester 0.005 Sodium (g) 0.1 0.1 * Provided by Nestle Company, São Paulo, Brazil Blood Sampling After fasting for 12 hours, blood samples were collected into tubes containing Ethylenediamine tetraacetic acid (EDTA). Plasma was immediately separated by centrifugation (1300 g , 15 min, 4 °C; RT6000B; Sorvall Instruments, DuPont Co, Newton, CT), and the following preservatives were added: 0.25% chloramphenicol plus 0.5% gentamycin (20 µL/mL), 2 mmol benzamidine/L (5 µL/mL), 10 mmol phenyl-methyl-sulfonyl fluoride/L (0.5 µL/mL), and aprotinin (0.5 µL/mL). For HDL-C measurements, plasma was mixed and kept at room temperature for 10 min and then centrifuged ( 700 g , 30 min, 4ºC). Aliquots (500 µL) were stored at -70ºC.Total plasma and serum were stored at -70ºC. All measurements were performed in duplicate at the end of the study. All samples from one subject were analyzed within the same analytical run. Serum Sterols Analyses Plasma precursors of cholesterol synthesis (desmosterol, lathosterol) and phytosterols (campesterol and sitosterol) were measured in samples (100 µL) added 5α-cholestane (1 µg) as the internal standard, hydrolyzed with KOH in ethanol (1 mol/l, 1 ml) at 60 °C (1 h) and extracted with hexane. Sterols were derivatized with a sylilating solution (pyridine and BSTFA (N,O-bis (trimethylsilyl) trifluoroacetamide) + 1% TMCS (trimethylchlorosilane) (1:1, v/v) (Supelco 33155-U) for 1 h at 60 °C [ 28 ]. The quantification was performed comparing the peak areas of the standard curve and corrected for internal standards. Plasma non-cholesterol sterols (µg) were expressed as ratio of plasma total cholesterol (mg). Statistical analysis Comparisons between the placebo and phytosterol groups were analysed by paired Student’s t test. The influence of degree of hypercholesterolemia over the PS response and PS response patterns related to LDL-C were analysed by unpaired Student’s t test. Data are shown as means and standard deviation. The analyses were performed utilizing the GraphPad Prisma version 4.00 and significance level considered as p < 0.05. Results The study was initiated with 40 subjects but two of them were excluded for presenting more than 5% of weight variation along the study. The body weight and the BMI of the participants remained unaltered throughout the study (Table 3 ). As demonstrated in several studies, PS reduced total cholesterol, LDL-C, apo B and triglycerides without affecting HDL-C plasma concentrations. As expected, PS supplementation increased plasma lathosterol as well as campesterol and β-sitosterol (indicating compliance to the diets). Lathosterol increased in plasma as a consequence of the blockade of the absorption of cholesterol exerted by PS ingestion. However, the lathosterol / phytosterols ratios decreased due to the higher absorption of PS. Table 3 Body weight, BMI, biochemical analysis, plasma sterol concentrations of moderately hypercholesterolemic patients. n Placebo Phytosterol p Body weight (kg) 38 64.9 ± 10.2 65.1 ± 10.3 0.08 BMI (kg/m 2 ) 38 25.4 ± 0.4 25.4 ± 0.4 ns Total cholesterol (mg/dL) 38 261 ± 7.1 244 ± 5.8 * < 0.001 HDL-C (mg/dL) 38 46 ± 1.7 48 ± 1.9 ns LDL-C (mg/dL) 38 183 ± 5.9 169 ± 5.2 * 0.001 ApoB (mg/dL) 38 126 ± 3.7 118 ± 3.2 * 0.006 Triglycerides (mg/dL) 38 154 ± 10 133 ± 7 * 0.008 Plasma sterols expressed as µg/mg cholesterol Lathosterol 38 1.53 ± 0.09 1.69 ± 0.06 * 0.012 Campesterol 38 1.96 ± 0.12 2.34 ± 0.11 * 0.02 β-sitosterol 38 1.64 ± 0.09 2.02 ± 0.09 * < 0.001 Lathosterol/campesterol ratio 38 0.85 ± 0.05 0.76 ± 0.03 * < 0.001 Lathosterol/β-sitosterol ratio 38 1.03 ± 0.05 0.88 ± 0.04 * < 0.001 BMI: body mass index; LDL-C: low-density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; apoB: apolipoprotein B. Data shown as means and standard deviation. Student’s t test. In order to investigate whether the degree of hypercholesterolemia influenced the PS response, patients were divided according to tertiles of LDL-C at baseline ( 187 mg/dL) (Table 4 ) . Placebo minus phytosterol data variations are expressed as delta values. PS intake effectively reduced LDL-C and apo B concentrations in both groups but failed to modify triglycerides concentrations Furthermore, serum concentration of lathosterol, campesterol and sitosterol were higher in the LDL-C 187 tertiles, but failed to change on PS feeding. Table 4 Patients according to the averages of LDL-C tertiles at baseline ( 187 mg/dL) LDL-C 187 p LDL (mg/dL) Placebo 150 ± 14 n = 13 215 ± 20 n = 12 < 0.0001 Phytosterol 148 ± 15 n = 13 192 ± 24 n = 12 < 0.0001 Delta LDL-C (%) -0.5 ± 13 -10.3 ± 12 ns Delta LDL-C (mg) -1.9 ± 18.1 -23.0 ± 26.1 0.0269 ApoB (mg/dL) Placebo 110 ± 10 n = 13 151 ± 22 n = 13 < 0.0001 Phytosterol 112 ± 14 n = 13 131 ± 22 n = 13 0.0120 Delta ApoB (%) 1.8 ± 10.1 -12.5 ± 10.2 0.0019 Delta ApoB (mg) 1.8 ± 11.5 -19.3 ± 17.5 0.0013 Triglycerides (mg/dL) Placebo 96 ± 7 n = 13 130 ± 14 n = 13 < 0.0001 Phytosterol 115 ± 38 n = 13 148 ± 44 n = 13 0.0472 Delta triglycerides (%) 22 ± 36 15 ± 38 ns Delta triglycerides (mg) 19 ± 42 18 ± 47 ns Lathosterol (µg/mg cholesterol) Placebo 1.689 ± 0.314 n = 11 1.372 ± 0.303 n = 12 0.0221 Phytosterol 1,887 ± 0,250 n = 11 1,522 ± 0,233 n = 12 0.0016 Delta lathosterol (%) 13,73 ± 15,42 14,15 ± 22,77 ns Delta lathosterol (µg/mg) 0,197 ± 0,214 0,150 ± 0,286 ns Campesterol (µg/mg cholesterol) Placebo 2.370 ± 0.633 n = 11 1.391 ± 0.345 n = 12 0.0002 Phytosterol 2,881 ± 0,754 n = 11 1,941 ± 0,518 n = 11 0.0028 Delta campesterol (%) 25,43 ± 32,30 40,71 ± 20,73 ns Delta campesterol (µg/mg) 0,511 ± 0,704 0,550 ± 0,280 ns Sitosterol (µg/mg cholesterol) Placebo 1.952 ± 0.445 n = 11 1.196 ± 0.283 n = 11 0.0001 Phytosterol 2,484 ± 0,518 n = 11 1,693 ± 0,451 n = 11 0.0011 Delta sitosterol (%) 30,16 ± 26,87 41,91 ± 17,95 ns Delta sitosterol (µg/mg) 0,532 ± 0,506 0,497 ± 0,242 ns LDL: low-density lipoprotein; apoB: apolipoprotein B. Placebo minus phytosterol data variations are expressed as delta values. Data shown as means and standard deviation. Unpaired Student’s t test. We also examined whether PS response patterns related to LDL-C response patterns: some patients were non-responders (n = 10), but most cases were responders (n = 27) (Table 5 ). Placebo minus phytosterol data variations are expressed as delta values. We found in the placebo phase lathosterol higher in non-responders than in responders to PS. However, on PS feeding the concentrations of lathosterol did not differ between the two groups. On the other hand, lathosterol percent variation on PS in relation to the placebo period did not vary in non-responders and increased in responders. This means that non-responders, because they have high synthesis before treatment, could not further expand synthesis on PS treatment. Responders synthesize less in the placebo phase but expand the synthesis rate on PS treatment. Table 5 Plasma sterols response patterns defined by LDL-C changes defining patients non-responders and responders to PS treatment. Non-responders (n = 10) Responders (n = 27) p LDL-C (mg/dL) Placebo 171 ± 24 191 ± 37 ns Phytosterol 184 ± 29 165 ± 32 ns Delta LDL-C (%) 8 ± 5 -13 ± 7 < 0.0001 Delta LDL-C (mg/dL) 14 ± 9 -26 ± 15 < 0.0001 Lathosterol (µg/mg cholesterol) Placebo 1,929 ± 0,954 1,463 ± 0,363 0.0379 Phytosterol 1,658 ± 0,411 1,686 ± 0,344 ns Delta lathosterol (%) -8 ± 16 18 ± 19 0.0009 Campesterol (µg/mg cholesterol) Placebo 2,242 ± 0,898 1,831 ± 0,610 ns Phytosterol 2,168 ± 0,582 2,401 ± 0,755 ns Delta campesterol (%) 3 ± 25 34 ± 26 0.0053 Sitosterol (µg/mg cholesterol) Placebo 1,958 ± 0,860 1,529 ± 0,469 ns Phytosterol 1,841 ± 0,532 2,075 ± 0,595 ns Delta sitosterol (%) 1 ± 26 38 ± 23 0.0007 LDL: low-density lipoprotein. Placebo minus phytosterol data variations are expressed as delta values. Data shown as means and standard deviation. Unpaired Student’s t test. Discussion As expected, the consumption of PS-enriched soy milk significantly lowered total cholesterol (-5.5%) and LDL-C (-7.6%). The very mild cholesterol reduction could be attributed to a small PS intake in this study as compared to other investigations [ 29 ] [ 30 ]. However, the blood cholesterol variation was intense enough to identify different patterns of metabolic changes. Furthermore, a wide variability in individual LDL-C plasma reduction in response to PS intake was previously reported by us [ 1 ]. PS also reduced apoB-LP likely belonging to LDL, but increased TG plasma concentrations as compared to placebo especially in participants presenting higher LDL-C concentrations at baseline. Present investigation confirms previous studies showing that the lathosterol-to-cholesterol ratio in serum predicted the serum cholesterol response to PS feeding where high basal cholesterol synthesis is associated with lack of response of plasma cholesterol [ 24 , 25 ], and contradicts another study in children in which dietary PS alters the concentration of PS in serum but not the serum concentration of cholesterol synthesis precursors [ 23 ]. In one study during the placebo period it was shown in the low cholesterol synthesis cases that high intestinal sitosterol absorption occurred on PS feeding [ 24 ] but was not mentioned in the other study [ 25 ]. Since the degree of cholesterol absorption indicated by plasma phytosterol concentration could influence cholesterol synthesis in the placebo phase and its response to PS intake, we measured plasma phytosterols concentrations before and after PS feeding. We noted that absorption markers did not differ between responders and non-responders in the placebo phase. Therefore, the difference in responses between the two groups is strictly dependent on the intensity of cholesterol synthesis. However, unlike the non-responders, responders are capable of increasing the absorption of PS most likely because there are small amounts of cholesterol in the intestinal lumen to compete for the intestinal absorption with the alimentary PS. We conclude that elevated synthesis during placebo in non-responders makes them resistant to further synthesis rise on PS treatment, whereas responders, because they have lower synthesis than non-responders in the placebo phase, are capable expanding synthesis under the effect of alimentary PS. Interestingly, in the placebo phase, as well as after ingestion of PS, the plasma concentrations of campesterol and sitosterol did not differ between the non-responders and the responder cases. However, as occurred for lathosterol, the percent variation of these markers of absorption on PS feeding over the placebo period was significantly greater in the responders than in the non-responders. This is compatible with the responders absorbing more PS than non-responders. Our data contribute to explain investigation in cases of metabolic syndrome in which decreased intestinal absorption of cholesterol is associated with lower efficiency of PS esters in reducing blood cholesterol although the cholesterol synthesis markers had not been measured [ 31 ]. Such a result may be consequent to elevated cholesterol synthesis in cases of metabolic syndrome [ 16 ]. In summary, responders absorbed more PS than non-responders likely resulting from responders delivering less endogenous cholesterol into the intestinal lumen that facilitates greater absorption of PS by the intestine. Abbreviations BMI body mass index BSTFA N,O-bis (trimethylsilyl) trifluoroacetamide EDTA ethylenediamine tetraacetic acid HDL-C high-density lipoproteins cholesterol LDL-C low-density lipoproteins cholesterol PS phytosterols TMCS trimethylchlorosilane Declarations Ethics approval and consent to participate The Ethics in Research Committee of the Hospital of the University of Sao Paulo Medical School approved the study protocol (CAPPesq n° 112/06). All participants were informed of the objectives of the protocol and signed an informed written consente. Consent for publication All the authors have consented for the publication of this study. Availability of data and materials The data used to support the findings of this study are included within the article. Additional data or information can be requested by contacting the corresponding author. Conflict of Interest The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results Funding This work was supported by UNILEVER (SP, Brazil) Author contribution VSN: Conceptualization, Methodology, Writing - Review & Editing. AOGI: Conceptualization, Writing - original draft, Investigation, Methodology; MSA, RPAB, RMM: Investigation, Methodology; GSF: Formal analysis; ERN: Formal analysis; ECRQ: Writing - review & editing; AMPL: Writing - review & editing, Supervision, Funding acquisition. Acknowledgements Not applicable References Lottenberg AMP, Nunes VS, Nakandakare ER, Neves M, Bernik M, Santos JE, et al. [Food phytosterol ester efficiency on the plasma lipid reduction in moderate hypercholesterolemic subjects]. Arquivos brasileiros de cardiologia. 2002. Acuff RV, Cai DJ, Dong ZP, Bell D. 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Effects of plant sterol and stanol ester consumption on lipid metabolism, antioxidant status and markers of oxidative stress, endothelial function and low-grade inflammation in patients on current statin treatment. European journal of clinical nutrition England. 2008;62:263–73. Bombo RPA, Afonso MS, Machado RM, Lavrador MSF, Nunes VS, Quintão ER, et al. Dietary phytosterol does not accumulate in the arterial wall and prevents atherosclerosis of LDLr-KO mice. Atherosclerosis. 2013;231. Hernandez-Mijares A, Banuls C, Jover A, Sola E, Bellod L, Martinez-Triguero ML, et al. Low intestinal cholesterol absorption is associated with a reduced efficacy of phytosterol esters as hypolipemic agents in patients with metabolic syndrome. Clinical nutrition (Edinburgh, Scotland). England. 2011;30:604–9. 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Nunes","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYFAC5gYGBgMI88AHIMHGTlALI1QLGzPDwRkQmhgtDBClzDxgawloMDh+sPFxRYGdvcH9/oOHbX5tk+djZmD88DEHj5Yzic2GZwySEzccY2Y4nNt327ANaJvkzG24tUg2JLZJNhgwJxiAtfTcZgRqYWPmxael/2H7zwaDenuwFsue2/YEtfBLJLYxNhgcZgQ7jOHH7UQitDxsBjrseOLMY8kGB3sbbie3MTM24/ULG3/ywY8Nf6rt+Q4ffPzhx5/btvPbmw9++IhHCypgbAOTDcSqB4E/pCgeBaNgFIyCkQIAkgZRROFVgBAAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6769-5412","institution":"Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"Sutti","lastName":"Nunes","suffix":""},{"id":537682,"identity":"caca4e1d-8bd9-4e39-bf9f-c26e83755cd5","order_by":2,"name":"Angela Oliveira Godoy Ilha","email":"","orcid":"","institution":"Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Angela","middleName":"Oliveira Godoy","lastName":"Ilha","suffix":""},{"id":537683,"identity":"0ab0c36f-54ef-444c-a852-4b15442cb431","order_by":3,"name":"Guilherme Silva Ferreira","email":"","orcid":"","institution":"LABORATORIO DE LIPIDES (LIM 10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guilherme","middleName":"Silva","lastName":"Ferreira","suffix":""},{"id":537684,"identity":"0ac08601-e7df-4c3b-b293-09b5d6d34043","order_by":4,"name":"Renata Paula Assis Bombo","email":"","orcid":"","institution":"LABORTATORIO DE LIPIDES (LIM 10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Renata","middleName":"Paula Assis","lastName":"Bombo","suffix":""},{"id":537685,"identity":"a2317d03-9800-4fda-b8fe-c28042941b99","order_by":5,"name":"Milessa Silva Afonso","email":"","orcid":"","institution":"LABORATORIO DE LIPIDES (LIM10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Milessa","middleName":"Silva","lastName":"Afonso","suffix":""},{"id":537686,"identity":"a20bdfe1-1dbc-4fac-9766-13d4c8aecb60","order_by":6,"name":"Roberta Marcondes Machado","email":"","orcid":"","institution":"LABORATORIO DE LIPIDES (LIM 10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Roberta","middleName":"Marcondes","lastName":"Machado","suffix":""},{"id":537687,"identity":"e98eae12-b2ec-45df-8de2-37450b1be06b","order_by":7,"name":"Edna Regina Nakandakare","email":"","orcid":"","institution":"LABORATORIO DE LIPIDES (LIM 10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Edna","middleName":"Regina","lastName":"Nakandakare","suffix":""},{"id":537688,"identity":"54a44cf4-a4ec-4964-8c3d-b8e274d3c346","order_by":8,"name":"Eder Carlos Rocha Quintão","email":"","orcid":"","institution":"LABORATORIO DE LIPIDES (LIM 10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eder","middleName":"Carlos Rocha","lastName":"Quintão","suffix":""},{"id":537689,"identity":"8d8bd6a0-266b-480e-a836-a19c8e8a783a","order_by":9,"name":"Ana Maria Maria Lottenberg","email":"","orcid":"","institution":"LABORATORIO DE LIPIDES (LIM 10), HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Maria Maria","lastName":"Lottenberg","suffix":""}],"badges":[],"createdAt":"2020-04-29 06:46:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-26174/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-26174/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":13501916,"identity":"9eb7dee6-768b-4999-94db-01f3412fe9ee","added_by":"auto","created_at":"2021-09-16 23:12:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":382105,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-26174/v1/045b0241-5398-464a-aba5-869ae210b60b.pdf"}],"financialInterests":"","formattedTitle":"Lathosterol in plasma measures cholesterol synthesis and identifies the efficiency of dietary phytosterols in reducing the plasma cholesterol concentration","fulltext":[{"header":"Introduction","content":" \u003cp\u003eIt is well known that phytosterols (PS) reduce plasma total cholesterol and low-density lipoproteins cholesterol (LDL-C) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] due to displacement of cholesterol from the intestinal lumen micelles [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and for exerting their molecular actions inside enterocytes and hepatocytes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, it was also demonstrated that PS could induce LDL receptor expression [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Because of the beneficial effects on lipid profile, the 2001 National Cholesterol Education Program (NCEP ATP-III) (National Cholesterol Education Program Expert Panel) included PS in the dietary treatment for moderate hypercholesterolemia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, after the publication of this guideline, some reports have shown that high PS plasma and tissue concentrations related to increase on cardiovascular risk [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Nevertheless, Bombo et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]clearly showed that LDL receptor knockout mice fed a high saturated fat diet supplemented with 2\u0026nbsp;g of PS did not accumulate sterols on aortic valve or arterial wall. On the other hand, PS treatment prevented atherosclerotic lesion development in hypercholesterolemic mice models [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePlasma concentrations of PS, and of non-cholesterol sterol precursors of cholesterol synthesis, respectively, markers of the intestinal cholesterol absorption and of the body\u0026rsquo;s cholesterol synthesis have been utilized as markers of atherosclerotic cardiovascular disease [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Nonetheless, objections of diverse nature have been raised on the interpretation of the results utilizing plasma PS measurements as markers of intestinal cholesterol absorption and non-cholesterol precursors as markers of cholesterol synthesis. In this regard, high plasma PS were reported inappropriate cholesterol absorption surrogates because PS in the diet lowered the intestinal cholesterol absorption rate [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Furthermore, in an investigation on moderate hypercholesterolemia, the plasma campesterol/cholesterol ratio did not differ between groups that absorb different amounts of cholesterol measured by the gold standard isotopic procedure [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, elevation of plasma PS may represent defect in the body's efficiency to re-excrete PS and not an increase in the intestinal absorption of dietary cholesterol. In this regard it is important to take into account that the biliary excretion of plasma PS was more efficient than of plasma cholesterol [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Retention of PS in plasma and other tissues may not be due to their increased absorption by intestinal mucosal cells. Consequently, it is questionable whether increased intestinal uptake of PS relates to premature atherosclerosis in humans. Accordingly, cardiovascular disease (CVD) mortality related reciprocally with PS (sitosterol) as a cholesterol absorption marker: the high desmosterol/sitosterol ratio suggested high cholesterol synthesis and low absorption associated with high total and CVD mortality [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Nonetheless, low serum lathosterol, but not absorption markers, had also been associated with increased CVD [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, as expected, increased excretion of endogenous cholesterol, which represents increased synthesis, was negatively associated with carotid intima-media thickness [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Consequently, the validity of the role on cardiovascular risk of the serum sterol synthesis and absorption markers remains questionable.\u003c/p\u003e \u003cp\u003eIn one study in children dietary PS altered the PS concentration in serum but not the concentrations of cholesterol synthesis precursors [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Contrarily, in one study on low cholesterol synthesis cases during the placebo period it was shown that high intestinal sitosterol absorption occurred on PS feeding [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] but the latter was not mentioned in the other study [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo investigate these previous discrepancies, we measured in plasma the concentrations of precursors of cholesterol synthesis and PS as markers of intestinal absorption of cholesterol in the placebo phase and after ingestion of PS.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubject recruitment\u003c/h2\u003e \u003cp\u003eThe individuals (n\u0026thinsp;=\u0026thinsp;38: female 31 and male 7) aged 38\u0026ndash;77\u0026nbsp;years were recruited in the Dyslipidemia Outpatient Unit of the Endocrinology and Metabolism Service of the Clinical Hospital of the University of Sao Paulo, Brazil; members of the staff of the University of Sao Paulo, Brazil were also included. The participants were invited for screening of body weight and height; blood samples were collected for lipids profile determination. The inclusion criteria were: body mass index (BMI) between 20 and 30\u0026nbsp;kg/m\u003csup\u003e2\u003c/sup\u003e; total cholesterol between 200\u0026ndash;300\u0026nbsp;mg/dL, LDL-C concentrations\u0026thinsp;\u0026ge;\u0026thinsp;130\u0026nbsp;mg/dL, and triglycerides\u0026thinsp;\u0026le;\u0026thinsp;250\u0026nbsp;mg/dL (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Exclusion criteria were: use of lipid-lowering medication or a prescribed diet in the last month; alcohol abuse or illicit drug users; pregnancy or breast feeding; smoking; diabetes mellitus, hypothyroidism, renal or hepatic diseases or participation in another lifestyle or pharmaceutical intervention studies. All subjects provided informed written consent. The Ethics in Research Committee of the Hospital of the University of Sao Paulo Medical School approved the study protocol (CAPPesq n\u0026deg; 112/06).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubjects characteristics at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (Kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245\u0026thinsp;\u0026plusmn;\u0026thinsp;34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141\u0026thinsp;\u0026plusmn;\u0026thinsp;53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e165\u0026thinsp;\u0026plusmn;\u0026thinsp;34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-C (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI, body mass index; LDL-C, low-density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThe present study was a randomized, double-blind, placebo-controlled dietary intervention trial with each study period lasting 4 weeks. Initially, all the participants were submitted to a 3-week run-in period in which they received the placebo product (soy milk) to test adherence to the protocol. After baseline period the individuals were randomly assigned to placebo or to phytosterol groups for 4 weeks; after that a reverse sequence was immediately carried out. Placebo group received 400\u0026nbsp;mL of soy milk daily; phytosterol group received 400\u0026nbsp;mL of soy milk enriched with 1.6\u0026nbsp;g of PS, as follow: 78% β-sitosterol-ester, 13% sitostanol-ester, 5.3% campesterol-ester and 0.5% campestanol-ester (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Blood samples were drawn for biochemical analysis from fasting participants on the last day of each period study. All participants were advised to maintain body weight and follow a normocaloric diet based on the NCEP-ATPIII recommendation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]: 30% of energy as fat, \u0026lt;\u0026thinsp;10% of energy as saturated fat, and \u0026lt;\u0026thinsp;300\u0026nbsp;mg cholesterol/day and was recommended not to consume products enriched with phytosterol during the study. Nutritional monitoring was carried out by a registered dietitian using a 24-hour dietary recall to ensure adherence to the prescribed diet and also to estimate the food intake. Soy milk was weekly supplied at the same day of the body weight measurement; patients were instructed to consume the soy milk or PS-enriched soy milk twice daily, at lunch and dinner.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSoy milk nutritional composition per portion (200\u0026nbsp;mL)*.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNutritional composition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSoy milk\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSoy milk\u0026thinsp;+\u0026thinsp;PS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnergy (kcal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e144\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal fat (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolyunsaturated fat\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonounsaturated fat\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaturated fat\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrans fatty acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCholesterol (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbohydrates (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal sugar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhytosterol (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ-sitosterol-ester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSitostanol-ester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCampesterol-ester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCampestanol-ester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e*\u003c/b\u003eProvided by Nestle Company, S\u0026atilde;o Paulo, Brazil\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003ch2\u003eBlood Sampling\u003c/h2\u003e \u003cp\u003eAfter fasting for 12 hours, blood samples were collected into tubes containing Ethylenediamine tetraacetic acid (EDTA). Plasma was immediately separated by centrifugation (1300\u0026nbsp;\u003cem\u003eg\u003c/em\u003e, 15\u0026nbsp;min, 4\u0026nbsp;\u0026deg;C; RT6000B; Sorvall Instruments, DuPont Co, Newton, CT), and the following preservatives were added: 0.25% chloramphenicol plus 0.5% gentamycin (20 \u0026micro;L/mL), 2\u0026nbsp;mmol benzamidine/L (5 \u0026micro;L/mL), 10\u0026nbsp;mmol phenyl-methyl-sulfonyl fluoride/L (0.5 \u0026micro;L/mL), and aprotinin (0.5 \u0026micro;L/mL). For HDL-C measurements, plasma was mixed and kept at room temperature for 10\u0026nbsp;min and then centrifuged (\u003cem\u003e700\u0026nbsp;g\u003c/em\u003e, 30\u0026nbsp;min, 4\u0026ordm;C). Aliquots (500\u0026nbsp;\u0026micro;L) were stored at -70\u0026ordm;C.Total plasma and serum were stored at -70\u0026ordm;C. All measurements were performed in duplicate at the end of the study. All samples from one subject were analyzed within the same analytical run.\u003c/p\u003e \u003ch2\u003eSerum Sterols Analyses\u003c/h2\u003e \u003cp\u003ePlasma precursors of cholesterol synthesis (desmosterol, lathosterol) and phytosterols (campesterol and sitosterol) were measured in samples (100 \u0026micro;L) added 5α-cholestane (1\u0026nbsp;\u0026micro;g) as the internal standard, hydrolyzed with KOH in ethanol (1\u0026nbsp;mol/l, 1\u0026nbsp;ml) at 60\u0026nbsp;\u0026deg;C (1\u0026nbsp;h) and extracted with hexane. Sterols were derivatized with a sylilating solution (pyridine and BSTFA (N,O-bis (trimethylsilyl) trifluoroacetamide)\u0026thinsp;+\u0026thinsp;1% TMCS (trimethylchlorosilane) (1:1, v/v) (Supelco 33155-U) for 1\u0026nbsp;h at 60\u0026nbsp;\u0026deg;C [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The quantification was performed comparing the peak areas of the standard curve and corrected for internal standards. Plasma non-cholesterol sterols (\u0026micro;g) were expressed as ratio of plasma total cholesterol (mg).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eComparisons between the placebo and phytosterol groups were analysed by paired Student\u0026rsquo;s t test. The influence of degree of hypercholesterolemia over the PS response and PS response patterns related to LDL-C were analysed by unpaired Student\u0026rsquo;s t test. Data are shown as means and standard deviation. The analyses were performed utilizing the GraphPad Prisma version 4.00 and significance level considered as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cp\u003eThe study was initiated with 40 subjects but two of them were excluded for presenting more than 5% of weight variation along the study. The body weight and the BMI of the participants remained unaltered throughout the study (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). As demonstrated in several studies, PS reduced total cholesterol, LDL-C, apo B and triglycerides without affecting HDL-C plasma concentrations. As expected, PS supplementation increased plasma lathosterol as well as campesterol and β-sitosterol (indicating compliance to the diets). Lathosterol increased in plasma as a consequence of the blockade of the absorption of cholesterol exerted by PS ingestion. However, the lathosterol / phytosterols ratios decreased due to the higher absorption of PS.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBody weight, BMI, biochemical analysis, plasma sterol concentrations of moderately hypercholesterolemic patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e261\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e244\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-C (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e169\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApoB (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e154\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlasma sterols expressed as \u0026micro;g/mg cholesterol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLathosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCampesterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ-sitosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLathosterol/campesterol ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLathosterol/β-sitosterol ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eBMI: body mass index; LDL-C: low-density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; apoB: apolipoprotein B. Data shown as means and standard deviation. Student\u0026rsquo;s t test.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn order to investigate whether the degree of hypercholesterolemia influenced the PS response, patients were divided according to tertiles of LDL-C at baseline (\u0026lt;\u0026thinsp;168\u0026nbsp;mg/dL and \u0026gt;\u0026thinsp;187\u0026nbsp;mg/dL) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Placebo minus phytosterol data variations are expressed as delta values. PS intake effectively reduced LDL-C and apo B concentrations in both groups but failed to modify triglycerides concentrations\u003c/p\u003e \u003cp\u003eFurthermore, serum concentration of lathosterol, campesterol and sitosterol were higher in the LDL-C\u0026thinsp;\u0026lt;\u0026thinsp;148 than in LDL-C\u0026thinsp;\u0026gt;\u0026thinsp;187 tertiles, but failed to change on PS feeding.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients according to the averages of LDL-C tertiles at baseline (\u0026lt;\u0026thinsp;168\u0026nbsp;mg/dL and \u0026gt;\u0026thinsp;187\u0026nbsp;mg/dL)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDL-C\u0026thinsp;\u0026lt;\u0026thinsp;168\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLDL-C\u0026thinsp;\u0026gt;\u0026thinsp;187\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLDL (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e215\u0026thinsp;\u0026plusmn;\u0026thinsp;20\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e148\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e192\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta LDL-C (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-10.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta LDL-C (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;18.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-23.0\u0026thinsp;\u0026plusmn;\u0026thinsp;26.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0269\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eApoB (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e110\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e151\u0026thinsp;\u0026plusmn;\u0026thinsp;22\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e131\u0026thinsp;\u0026plusmn;\u0026thinsp;22\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta ApoB (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta ApoB (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-19.3\u0026thinsp;\u0026plusmn;\u0026thinsp;17.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e115\u0026thinsp;\u0026plusmn;\u0026thinsp;38\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e148\u0026thinsp;\u0026plusmn;\u0026thinsp;44\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0472\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta triglycerides (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u0026thinsp;\u0026plusmn;\u0026thinsp;36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta triglycerides (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u0026thinsp;\u0026plusmn;\u0026thinsp;42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026thinsp;\u0026plusmn;\u0026thinsp;47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLathosterol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/mg cholesterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.689\u0026thinsp;\u0026plusmn;\u0026thinsp;0.314\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.372\u0026thinsp;\u0026plusmn;\u0026thinsp;0.303\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0221\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,887\u0026thinsp;\u0026plusmn;\u0026thinsp;0,250\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,522\u0026thinsp;\u0026plusmn;\u0026thinsp;0,233\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta lathosterol (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13,73\u0026thinsp;\u0026plusmn;\u0026thinsp;15,42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14,15\u0026thinsp;\u0026plusmn;\u0026thinsp;22,77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta lathosterol (\u0026micro;g/mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,197\u0026thinsp;\u0026plusmn;\u0026thinsp;0,214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,150\u0026thinsp;\u0026plusmn;\u0026thinsp;0,286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCampesterol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/mg cholesterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.370\u0026thinsp;\u0026plusmn;\u0026thinsp;0.633\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.391\u0026thinsp;\u0026plusmn;\u0026thinsp;0.345\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,881\u0026thinsp;\u0026plusmn;\u0026thinsp;0,754\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,941\u0026thinsp;\u0026plusmn;\u0026thinsp;0,518\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta campesterol (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25,43\u0026thinsp;\u0026plusmn;\u0026thinsp;32,30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40,71\u0026thinsp;\u0026plusmn;\u0026thinsp;20,73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta campesterol (\u0026micro;g/mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,511\u0026thinsp;\u0026plusmn;\u0026thinsp;0,704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,550\u0026thinsp;\u0026plusmn;\u0026thinsp;0,280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSitosterol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/mg cholesterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.952\u0026thinsp;\u0026plusmn;\u0026thinsp;0.445\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.196\u0026thinsp;\u0026plusmn;\u0026thinsp;0.283\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,484\u0026thinsp;\u0026plusmn;\u0026thinsp;0,518\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,693\u0026thinsp;\u0026plusmn;\u0026thinsp;0,451\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta sitosterol (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30,16\u0026thinsp;\u0026plusmn;\u0026thinsp;26,87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41,91\u0026thinsp;\u0026plusmn;\u0026thinsp;17,95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta sitosterol (\u0026micro;g/mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,532\u0026thinsp;\u0026plusmn;\u0026thinsp;0,506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,497\u0026thinsp;\u0026plusmn;\u0026thinsp;0,242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eLDL: low-density lipoprotein; apoB: apolipoprotein B. Placebo minus phytosterol data variations are expressed as delta values. Data shown as means and standard deviation. Unpaired Student\u0026rsquo;s t test.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe also examined whether PS response patterns related to LDL-C response patterns: some patients were non-responders (n\u0026thinsp;=\u0026thinsp;10), but most cases were responders (n\u0026thinsp;=\u0026thinsp;27) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Placebo minus phytosterol data variations are expressed as delta values. We found in the placebo phase lathosterol higher in non-responders than in responders to PS. However, on PS feeding the concentrations of lathosterol did not differ between the two groups. On the other hand, lathosterol percent variation on PS in relation to the placebo period did not vary in non-responders and increased in responders. This means that non-responders, because they have high synthesis before treatment, could not further expand synthesis on PS treatment. Responders synthesize less in the placebo phase but expand the synthesis rate on PS treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma sterols response patterns defined by LDL-C changes defining patients non-responders and responders to PS treatment.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-responders\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResponders\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLDL-C (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e171\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e191\u0026thinsp;\u0026plusmn;\u0026thinsp;37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184\u0026thinsp;\u0026plusmn;\u0026thinsp;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e165\u0026thinsp;\u0026plusmn;\u0026thinsp;32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta LDL-C (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-13\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta LDL-C (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-26\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLathosterol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/mg cholesterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,929\u0026thinsp;\u0026plusmn;\u0026thinsp;0,954\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,463\u0026thinsp;\u0026plusmn;\u0026thinsp;0,363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0379\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,658\u0026thinsp;\u0026plusmn;\u0026thinsp;0,411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,686\u0026thinsp;\u0026plusmn;\u0026thinsp;0,344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta lathosterol (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCampesterol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/mg cholesterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,242\u0026thinsp;\u0026plusmn;\u0026thinsp;0,898\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,831\u0026thinsp;\u0026plusmn;\u0026thinsp;0,610\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,168\u0026thinsp;\u0026plusmn;\u0026thinsp;0,582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,401\u0026thinsp;\u0026plusmn;\u0026thinsp;0,755\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta campesterol (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSitosterol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/mg cholesterol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,958\u0026thinsp;\u0026plusmn;\u0026thinsp;0,860\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,529\u0026thinsp;\u0026plusmn;\u0026thinsp;0,469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhytosterol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,841\u0026thinsp;\u0026plusmn;\u0026thinsp;0,532\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,075\u0026thinsp;\u0026plusmn;\u0026thinsp;0,595\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ens\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta sitosterol (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eLDL: low-density lipoprotein. Placebo minus phytosterol data variations are expressed as delta values. Data shown as means and standard deviation. Unpaired Student\u0026rsquo;s t test.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eAs expected, the consumption of PS-enriched soy milk significantly lowered total cholesterol (-5.5%) and LDL-C (-7.6%). The very mild cholesterol reduction could be attributed to a small PS intake in this study as compared to other investigations [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. However, the blood cholesterol variation was intense enough to identify different patterns of metabolic changes. Furthermore, a wide variability in individual LDL-C plasma reduction in response to PS intake was previously reported by us [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. PS also reduced apoB-LP likely belonging to LDL, but increased TG plasma concentrations as compared to placebo especially in participants presenting higher LDL-C concentrations at baseline.\u003c/p\u003e \u003cp\u003ePresent investigation confirms previous studies showing that the lathosterol-to-cholesterol ratio in serum predicted the serum cholesterol response to PS feeding where high basal cholesterol synthesis is associated with lack of response of plasma cholesterol [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and contradicts another study in children in which dietary PS alters the concentration of PS in serum but not the serum concentration of cholesterol synthesis precursors [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In one study during the placebo period it was shown in the low cholesterol synthesis cases that high intestinal sitosterol absorption occurred on PS feeding [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] but was not mentioned in the other study [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Since the degree of cholesterol absorption indicated by plasma phytosterol concentration could influence cholesterol synthesis in the placebo phase and its response to PS intake, we measured plasma phytosterols concentrations before and after PS feeding. We noted that absorption markers did not differ between responders and non-responders in the placebo phase. Therefore, the difference in responses between the two groups is strictly dependent on the intensity of cholesterol synthesis. However, unlike the non-responders, responders are capable of increasing the absorption of PS most likely because there are small amounts of cholesterol in the intestinal lumen to compete for the intestinal absorption with the alimentary PS. We conclude that elevated synthesis during placebo in non-responders makes them resistant to further synthesis rise on PS treatment, whereas responders, because they have lower synthesis than non-responders in the placebo phase, are capable expanding synthesis under the effect of alimentary PS.\u003c/p\u003e \u003cp\u003eInterestingly, in the placebo phase, as well as after ingestion of PS, the plasma concentrations of campesterol and sitosterol did not differ between the non-responders and the responder cases. However, as occurred for lathosterol, the percent variation of these markers of absorption on PS feeding over the placebo period was significantly greater in the responders than in the non-responders. This is compatible with the responders absorbing more PS than non-responders. Our data contribute to explain investigation in cases of metabolic syndrome in which decreased intestinal absorption of cholesterol is associated with lower efficiency of PS esters in reducing blood cholesterol although the cholesterol synthesis markers had not been measured [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Such a result may be consequent to elevated cholesterol synthesis in cases of metabolic syndrome [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In summary, responders absorbed more PS than non-responders likely resulting from responders delivering less endogenous cholesterol into the intestinal lumen that facilitates greater absorption of PS by the intestine.\u003c/p\u003e "},{"header":"Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eBSTFA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eN,O-bis (trimethylsilyl) trifluoroacetamide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eEDTA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eethylenediamine tetraacetic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eHDL-C\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh-density lipoproteins cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eLDL-C\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elow-density lipoproteins cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ephytosterols\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTMCS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etrimethylchlorosilane\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003eThe Ethics in Research Committee of the Hospital of the University of Sao Paulo Medical School approved the study protocol (CAPPesq n\u0026deg; 112/06). All participants were informed of the objectives of the protocol and signed an informed written consente.\u003c/p\u003e\u003ch2\u003eConsent for publication\u003c/h2\u003e\u003cp\u003eAll the authors have consented for the publication of this study.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\u003cp\u003eThe data used to support the findings of this study are included within the article. Additional data or information can be requested by contacting the corresponding author.\u003c/p\u003e \u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results\u003c/p\u003e \u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by UNILEVER (SP, Brazil)\u003c/p\u003e \u003ch2\u003eAuthor contribution\u003c/h2\u003e \u003cp\u003eVSN: Conceptualization, Methodology, Writing - Review \u0026amp; Editing. AOGI: Conceptualization, Writing - original draft, Investigation, Methodology; MSA, RPAB, RMM: Investigation, Methodology; GSF: Formal analysis; ERN: Formal analysis; ECRQ: Writing - review \u0026amp; editing; AMPL: Writing - review \u0026amp; editing, Supervision, Funding acquisition.\u003c/p\u003e \u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e "},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003eLottenberg AMP, Nunes VS, Nakandakare ER, Neves M, Bernik M, Santos JE, et al. [Food phytosterol ester efficiency on the plasma lipid reduction in moderate hypercholesterolemic subjects]. Arquivos brasileiros de cardiologia. 2002.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eAcuff RV, Cai DJ, Dong ZP, Bell D. The lipid lowering effect of plant sterol ester capsules in hypercholesterolemic subjects. 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Clinical chemistry United States. 1972;18:499\u0026ndash;502.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eNunes VS, Lean\u0026ccedil;a CC, Panzoldo NB, Parra E, Cazita PM, Nakandakare ER, et al. HDL-C concentration is related to markers of absorption and of cholesterol synthesis: Study in subjects with low vs. high HDL-C. Clinica Chimica Acta. 2011;412.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eDe Jong A, Plat J, Bast A, Godschalk RWL, Basu S, Mensink RP. Effects of plant sterol and stanol ester consumption on lipid metabolism, antioxidant status and markers of oxidative stress, endothelial function and low-grade inflammation in patients on current statin treatment. European journal of clinical nutrition England. 2008;62:263\u0026ndash;73.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eBombo RPA, Afonso MS, Machado RM, Lavrador MSF, Nunes VS, Quint\u0026atilde;o ER, et al. Dietary phytosterol does not accumulate in the arterial wall and prevents atherosclerosis of LDLr-KO mice. Atherosclerosis. 2013;231.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHernandez-Mijares A, Banuls C, Jover A, Sola E, Bellod L, Martinez-Triguero ML, et al. Low intestinal cholesterol absorption is associated with a reduced efficacy of phytosterol esters as hypolipemic agents in patients with metabolic syndrome. Clinical nutrition (Edinburgh, Scotland). England. 2011;30:604\u0026ndash;9.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cholesterol, lathosterol, phytosterols, diet ","lastPublishedDoi":"10.21203/rs.3.rs-26174/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-26174/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBecause the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol measured by the gold standard isotopic procedure we investigated whether the intestinal absorption of phytosterols (PS) depends on the body's cholesterol synthesis rate.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e38 volunteers (58\u0026thinsp;\u0026plusmn;\u0026thinsp;12 years; low-density lipoprotein cholesterol (LDL-C)\u0026thinsp;\u0026ge;\u0026thinsp;130\u0026nbsp;mg/dL) were randomly assigned to consume 400\u0026nbsp;mL/day of soy milk or soy milk\u0026thinsp;+\u0026thinsp;PS (1.6\u0026nbsp;g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and markers of phytosterol (PS) absorption and non-cholesterol sterol synthesis precursors measured.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePS treatment reduced plasma total cholesterol concentration (-5,5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), LDL-C (-7.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), triglycerides (-13.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0085), and apolipoprotein B (apo B) (-6.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.008), without changing high density lipoprotein cholesterol (HDL-C concentration). The lathosterol-to-cholesterol ratio in serum predicted the serum cholesterol response to PS feeding where high basal cholesterol synthesis was associated with lack of response of plasma cholesterol to PS in the diet. Cholesterol synthesis being elevated in the placebo phase in non-responders to dietary PS indicated they were resistant to further synthesis rise, whereas responders, because they have lower synthesis rate than non-responders in the placebo phase, are capable expanding synthesis under the effect of alimentary PS.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eresponders absorbed more PS than non-responders likely resulting from responders delivering less endogenous cholesterol than non-responders into the intestinal lumen that facilitates greater absorption of PS by the intestine.\u003c/p\u003e","manuscriptTitle":"Lathosterol in plasma measures cholesterol synthesis and identifies the efficiency of dietary phytosterols in reducing the plasma cholesterol concentration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-05-07 17:51:45","doi":"10.21203/rs.3.rs-26174/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8ffe1629-e068-4f93-9a82-6df6553293d9","owner":[],"postedDate":"May 7th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":95202,"name":"Cardiac \u0026 Cardiovascular Systems"},{"id":95203,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2020-05-07T17:51:48+00:00","versionOfRecord":[],"versionCreatedAt":"2020-05-07 17:51:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-26174","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-26174","identity":"rs-26174","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}