Abstract
Cardiovascular disease is a major health problem in developed countries although its incidence is relatively lower in Mediterranean countries which is partly ascribed to dietary habits. Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (c-LDL), increases cardiovascular disease. Phytosterols are bioactive compounds, found in all vegetable foods, which inhibit intestinal cholesterol absorption and, therefore, have a serum cholesterollowering effect. Intestinal cholesterol absorption is a multistep process where, plant sterols and stanols may act:a) attenuating the NPC1L1 gene expression, which may result in a lower cholesterol uptake from the lumen;b) lowering the cholesterol esterification rate by the ACAT2 (acyl-CoA cholesterol acyltransferase) and, consequently, the amount of cholesterol secreted via the chylomicrons andc) upregulating the expression of ABC-transporters ABCG5 and ABCG8 in intestinal cells, which may result in an increased excretion of cholesterol by the enterocyte back in the lumen. Many clinical trials proved that commercial products enriched with phytosterols reduce cholesterol levels. Likewise, recent studies show that phytosterols present in natural food matrices are also effective and could be an important component of cardioprotective dietary patterns such as the Mediterranean diet.
Resumen
Le enfermedad cardiovascular es un problema de salud importante en los países desarrollados, aunque su incidencia es relativamente menor en los países mediterráneos lo que es parcialmente atribuible a los hábitos dietéticos. Existen evidencias epidemiológicas que muestran que el colesterol sérico elevado, específicamente el colesterol ligado a las lipoproteínas de baja densidad (c-LDL), incrementa la enfermedad cardiovascular. Los fitosteroles son compuestos bioactivos, presentes en todos los alimentos de origen vegetal, que inhiben la absorción intestinal de colesterol y, por lo tanto, tienen un efecto reductor en el colesterol sérico. La absorción intestinal de colesterol es un proceso multi-etapa donde los esteroles y estanoles vegetales pueden actuar de diversas formas:a) atenuando la expresión del gen NPC1L1, lo que puede suponer una disminución del ingreso de colesterol desde el lumen intestinal;b) disminuyendo la tasa de esterificación del colesterol por la ACAT2 (acil-CoA colesterol aciltransferasa) y, en consecuencia, la cantidad de colesterol excretada vía quilomicrones yc) aumentando la expresión de los ABC-transportadores ABCG5 y ABCG8 en las células intestinales, lo que puede derivar en una excreción incrementada de colesterol desde el enterocito hacia el lumen. Diversos ensayos clínicos han demostrado que los productos comerciales enriquecidos con fitosteroles reducen los niveles de colesterol. Sin embargo, estudios recientes muestran que los fitosteroles presentes en matrices alimentarias naturales también pueden ser bioactivos y podrían ser un componente importante de los patrones dietéticos cardioprotectores como es la dieta Mediterránea.
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References
Ahrens, E.H., Jr., Boucher, C.A. (1978): The composition of a simulated American diet.J Am Diet Assoc,73, 613–620.
Altmann, S.W., Davis, H.R.J., Zhu, L.J., Yao, X., Hoos, L.M., Tetzloff, G., Iyer, S.P., Maguire, M., Golovko, A., Zeng, M., Wang, L., Murgolo, N., Graziano, M.P. (2004): Niemann-Pick C1-like 1 protein is critical for intestinal cholesterol absorption.Science,303, 1201–1204.
Andersson, S.W., Skinner, J., Ellegärd, L., Welch, A.A., Bingham, S., Mulligan, A., Andersson, H., Khaw, K.T. (2004): Intake of dietary plant sterols is inversely related to serum cholesterol concentration in men and women in the EPIC Norfolk population: a cross-sectional study.Eur J Clin Nutr,58, 1378–1385.
Berger, A., Jones, P.J., Abumweis, S.S. (2004): Plant sterols: factors affecting their efficacy and safety as functional food ingredients.Lipids Health Dis,7, 3–5.
Bosner, M.S., Lange, L.G., Stenson, W.F., Ostlund, R.E. Jr. (1999): Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry.J Lipid Res,40, 302–308.
Calpe-Berdiel, L., Escola-Gil, J. C., Blanco-Vaca, F. (2008): New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism.Atherosclerosis. doi:10.1016/j.atherosclerosis.2008.06.026.
Cerqueira, M.T., Fry, M.M., Connor, W.E. (1979): The food and nutrient intakes of the Tarahumara Indians of Mexico.Am J Clin Nutr,32, 905–915.
De Jong, A., Plat, J., Mensink, R.P. (2003): Metabolic effects of plant sterols and stanols.J Nutr Bioch,14, 362–369.
De Vries, J.H.M., Jansen, A., Kromhout, D., van de Bovenkcamp, P., van Staveren, W.A., Mensink, R.P., Katan, M.B. (1997): The fatty acid and sterol content of food composites of middle-aged men in seven countries.J Food Comp Anal,10, 115–141.
Duan, L.P., Wang, H.H., Wang, D.Q.H. (2004): Cholesterol absorption is mainly regulated by the jejunal and ileal ATP-binding cassette sterol efflux transporters ABCG5 and ABCG8 in mice.J Lipid Res,45, 1312–1323.
Estruch, R., Martínez-González, M.A., Corella, D., Salas-Salvadó, J., Ruiz-Gutiérrez, V., Covas, M.I., Fiol, M., Gómez-Gracia, E., López-Sabater, M.C., Vinyoles, E., Arós, F., Conde, M., Lahoz, C., Lapetra, J., Sáez, G., Ros, E. (2006): Effects of Mediterranean-Style Diet on cardiovascular risk factors: a randomized trial.Ann Intern Med,145, 1–11.
Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. (2001): Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel III).JAMA,285, 2486–2497.
Field, F.J., Born, E., Mathur, S.N. (2004): Stanols decrease plasma cholesterol independently of intestinal ABC sterol transporters and Niemann-Pick C1-like 1 protein gene expression.J Lipid Res,45, 2252–2259.
Friday, K.E. (2003): Aggressive lipid management for cardiovascular prevention: evidence for clinical trials.Exp Biol Med,228, 769–778.
García-Otín, A.L., Cofan, M., Junyent, M., Recalde, D., Cenarro, A., Pocovi, M., Ros, E., Civeira, F. (2007): Increased intestinal cholesterol absorption in autosomal dominant hypercholesterolemia and no mutations in the Low-Density Lipoprotein receptor or Apolipoprotein B genes.J Clin Endocrinol Metab,92, 3667–3673.
Grundy, S.M. (1983) Absorption and metabolism of dietary cholesterol.Annu Rev Nutr,3, 71–96.
Heinmann, T., Kullak-Ublick, G.A., Pietruck, B., von Bergmann, K. (1991): Mechanisms of action of plant sterols on inhibition of cholesterol absorption. Comparison of sitosterol and sitostanol.Eur J Clin Pharmacol,40, S59-S63.
Hirai, K., Shimazu, C., Takezoe, R., Ozeki, Y. (1986): Cholesterol, phytosterol and polyunsaturated fatty acid levels in 1982 and 1957 Japanese diets.J Nutr Sci Vitaminol,32, 363–372.
Howell, T.J., MacDougall, D.E., Jones, P.J.H. (1998): Phytosterols partially explain differences in cholesterol metabolism caused by corn or olive oil feeding.J Lipid Res,39, 892–900.
Igel, M., Giesa, U., Lutjohann, D., von Bergmann, K. (2003): Comparison of the intestinal uptake of cholesterol, plant sterols and stanols in mice.J Lipid Res,44, 533–538.
Ikeda, I., Tanabe, Y., Sugano, M. (1989): Effects of sitosterol and sitostanol on micellar solubility of cholesterol.J Nutr Sci Vitaminol (Tokyo) 35, 361–369.
Jiménez-Escrig, A.J., Santos-Hidalgo, A.B., Saura-Calixto, F. (2006): Common sources and estimated intake of plant sterols in the Spanish diet.J Agric Food Chem,54, 3462–3471.
Kaneko, E., Matsuda, M., Yamada, Y., Tachibana, Y, Shimomura, I., Makishima, M. (2003): Induction of intestinal ATP-binding cassette transporters by a phytosterols-derived Liver X receptor agonist.J Biol Chem,278, 36091–36098.
Kassis, A.N., Vanstone, C.A., Abumweis, S.S., Jones, P.J.H. (2008): Efficacy of plant sterols is not influenced by dietary cholesterol intake in hypercholesterolemic individuals.Metabolism,57, 339–346.
Katan, M.B., Grundy, S.M., Jones, P., Law, M., Miettinen, T., Paoletti, R. (2003): Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels.Mayo Clin Proc,78, 965–978.
Kempen, H.J.M., de Knijff, P., Boomsma, D.I., van der Voort, H.A., Gevers Leuven, J.A., Havekes, L. (1991): Plasma levels of lathosterol and phytosterols in relation to age, sex, anthropometric parameters, plasma lipids and apolipoprotein E phenotype in 160 Dutch families.Metabolism,40, 604–611.
Kerckhoffs, D.A.J.M., Brouns, F., Hornstra, G, Mensink, R.P. (2002): Effects on the human serum lipoprotein profile of beta-glucan, soy protein and isoflavones, plant sterols and stanols, garlic and tocotrienols.J Nutr,132, 2494–2505
Kesäniemi, Y.A., Miettinen, T.A. (1987): Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population.Eur J Clin Invest,17, 391–395.
Klingberg, S., Andersson, H., Mulligan, A., Bhaniani, A., Welch, A., Bingham, S., Khaw, K.T., Andersson, S., Ellegärd, L. (2008): Food sources of plant sterols in the EPIC Norfolk population.Eur J Clin Nutr,62, 695–703.
Klingberg, S., Ellegärd, L., Johansson, I., Hallmans, G., Weinehall, L., Andersson, H., Winkvist, A. (2008): Inverse relation between dietary intake of naturally occurring plant sterols and serum cholesterol in northern Sweden.Am J Clin Nutr,87, 993–1001.
Lammert, F., Wang, D.Q. (2005): New insights into the genetic regulation of intestinal cholesterol absorption.Gastroenterology,129, 718–734
Law, M. (2000): Plant sterol and stanol margarines and health.BMJ,320, 861–864.
Lee, R. G., Willingham, M.C., Davis, M.A., Skinner, K.A., Rudel, L.L. (2000): Differential expression of ACAT1 and ACAT2 among cells within liver, intestine, kidney and adrenal of nonhuman primates.J Lipid Res,41, 1991–2001.
Levy, E., Spahis, S., Sinnett, D., Peretti, N., Maupas-Schwalm, F., Delvin, E., Lambert, M., Lavoie, M. A. (2007): Intestinal cholesterol transport proteins: an update and beyond.Curr Opin Lipidol,18, 310–318.
Lichtenstein, A.H. (2006): Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein patterns.J Lipid Res,47, 1661–1667.
Ling, W.H., Jones, P.J. H. (1995): Dietary phytosterols: a review of metabolism, benefits and side effects.Life Sci,57, 195–206.
Matthan, N.R., Lichtenstein, A.H. (2004): Appraches to measuring cholesterol absorption in humans.Atherosclerosis,174, 197–205.
Miettinen, T.A., Gylling, H., Raitakari, O.T., Hallikainen, M., Viikari, J. (2008): Adolescent cholesterol metabolism predicts coronary risk factors at middle age: the Cardiovascular Risk in Young Finns Study.Transl Res,151, 260–266.
Miettinen, T.A., Gylling, H., Viikari, J., Lehtimäki, T., Taitakari, O.T. (2008): Synthesis and absorption of cholesterol in Finnish boys by serum non-cholesterol sterols. The cardiovascular risk in young Finns study.Atherosclerosis,200, 177–183.
Miettinen, T.A., Tilvis, R.S., Kesäniemi, A. (1990): Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am J Epidemiol,131, 20–31.
Miettinen, T.A., Tilvis, R.S., Kesäniemi YA. (1989): Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged men.Metabolism,38, 136–40.
Miettinen, T.A., Gylling, H. (2000): Cholesterol absorption efficiency and sterol metabolism in obesity.Atherosclerosis,153, 241–248.
Miettinen, T.A., Kesaniemi, Y.A. (1989): Cholesterol absorption: regulation of cholesterol synthesis and elimination and within-population variations of serum cholesterol levels.Am J Clin Nutr,49, 629–635.
Miettinen, T.A., Gylling H. (1999): Regulation of cholesterol metabolism by dietary plant sterols.Curr Opin Lipidol,10, 9–14.
Millen, B.E., Franz, M.M., Quatromoni, P.A., Gagnon, D.R., Sonnenberg, L.M., Ordovas, J.M., Wilson, P.W., Schaefer, E.J., Cupples, L.A. (1996): Diet and plasma lipids in women. I. Macronutrients and plasma total and low-density lipoprotein cholesterol in women: the Framingham nutrition studies.J Clin Epidemiol,49, 657–663.
Moghadasian, M.H., Frohlich, J.J. (1999): Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence.Am J Med,107, 588–594.
Morton, G.M., Lee, S.M., Buss, D.H., Lawrance, P. (1995): Intakes and major dietary sources of cholesterol and phytosterols in the British diet.J Hum Nutr Diet,8, 429–440.
National Statistics Institute, Spain. Mortality statistics: Cause of death. www.ine.es/inebmenu/ indice.htm (consulted in September 2008).
Nissinen, M.J., Gylling, H., Miettinen, T.A. (2008): Responses of surrogate markers of cholesterol absorption and synthesis to changes in cholesterol metabolism during various amounts of fat and cholesterol feeding among healthy men.Br J Nutr,99, 370–378.
Normen, A.L., Brants, H.A., Voorrips, L.E., Andersson, H.A., Van den Brandt, P.A., Goldbohm, R.A. (2001): Plant sterol intakes and colorectal cancer risk in the Netherlands Cohort Study on Diet and Cancer.Am J Clin Nutr,74, 141–148.
Ostlund, R.E., Jr. (2007): Phytosterols, cholesterol absorption and healthy diets.Lipids,42, 41–45
Ostlund, R.E. Jr. (2002): Phytosterols in human nutrition.Annu Rev Nutr,22, 533–539.
Ostlund, R.E. Jr., McGill, J.B., Zeng, C.M., Covey, D.F., Stearns, J., Stenson, W.F., Spilburg, C.A. (2002): Gastrointestinal absorption and plasma kinetics of soy Δ5-phytosterols and phytostanols in humans.Am J Physiol Endocrinol Metab,282, 911–916.
Ostlund, R.E. Jr. Racette, S.B., Okeke, A., Stenson, W.F. (2002): Phytosterols that are naturally present in commercial corn oil significantly reduce cholesterol absorption in humans.Am J Clin Nutr,75, 1000–1004.
Ostlund, R. E., Jr, Racette, S.B., Stenson, W.F. (2003): Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ.Am J Clin Nutr,77, 1385–1389.
Patel, M.D., Thompson, P.D. (2006): Phytosterols and vascular disease.Atherosclerosis,186, 12–19.
Patel, S.B. (2008): Plant sterols and stanols: their role in health and disease.J Clin Lipidol,2, S11-S19.
Piironen, V., Lindsay, D.G., Miettinen, T.A., Toivo, J., Lampi A.M. (2000): Plant sterols: biosynthesis, biological function and their importance to human nutrition.J Sci Food Agric,80, 939–966.
Plat, J., Mensink, R.P. (2005): Plant stanol and sterol esters in the control of blood cholesterol levels: mechanism and safety aspects.Am J Cardiol, 96, 15D-22D.
Plat, J., Mensink, R.P. (2002): Effects of plant stanol esters on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase mRNA expression in mononuclear blood cells of healthy men and women.FASEB J,16, 258–260.
Plat, J., van Onselen, E.N., van Heugten, M.M., Mensink, R.P. (2000) Effects on serum lipids, lipoproteins and fat soluble antioxidant concentrations of consumption frequency of margarines and shortenings enriched with plant stanol esters.Eur J Clin Nutr,54, 671–677.
Pollak, O.J. (1953): Reduction of blood cholesterol in man.Circulation,7, 702–706.
Ros, E. (2000): Intestinal absorption of triglyceride and cholesterol. Dietary and pharmacological inhibition to reduce cardiovascular risk.Atherosclerosis,151, 357–379.
Sehayek, E., Nath, C., Heinemann, T., McGee, M., Seidman, C.E., Samuel, P., Breslow, J.L. (1998): U-shape relationship between change in dietary cholesterol absorption and plasma lipoprotein responsiveness and evidence for extreme interindividual variation in dietary cholesterol absorption in humans.J Lipid Res,39, 2415–2422.
Spanish Atherosclerosis Society. Cardiovascular diseases and their risk factors in Spain: facts and figures. Report 2007. www.searteriosclerosis.org (consulted in November 2008).
Theuwissen, E., Mensink, R.P. (2008): Water-soluble fibers and cardiovascular disease.Physiol Behav,94, 285–292.
Tilvis, R.S., Miettinen, T.A. (1986): Serum plant sterols and their relation to cholesterol absorption.Am J Clin Nutr,43, 92–97.
Valenzuela, A., Ronco, A.M. (2004): Phytosterols and phytostanols: natural allied for the protection of cardiovascular health.Rev Chil Nutr,21(S1), 161–169.
Valsta, L.M., Lemström, A., Ovaskainen, M.L., Lampi, A.M., Toivo, J., Korhonen, T., Piironen, V. (2004): Estimation of plant sterol and cholesterol intake in Finland: quality of new values and their effect on intake.Brit J Nutr,92, 671–678.
Van Horn, L., McCoin, M., Kris-Etherton, P.M., Burke, F., Carson, J.A., Champagne, C.M., Karmally, W., Sikand, G. (2008): The evidence for dietary prevention and treatment of cardiovascular disease.J Am Diet Assoc,108, 287–331.
Verger, P., Ireland, J., Møller, A., Abravicius, J.A., De Henauw, S., Naska, A. (2002): Improvement of comparability of dietary intake assessment using currently available individual food consumption surveys.Eur J Clin Nutr,56, S18-S24.
Von Bergmann, K., Sudhop, T., Lütjohann, D. (2005): Cholesterol and plant sterol absorption: recent insights.Am J Cardiol,96, 10D-14D.
Wang, D.Q. (2007): Regulation of intestinal cholesterol absorption.Annu Rev Physiol,69, 221–248.
Weststrate, J.A., Ayesh, R., Bauer-Plank, C., Drewitt, P.N. (1999): Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a controlled diet either with or without a phytosterol esterenriched margarine.Food Chem Toxicol,37, 1063–1071.
World Health Organization. www.who.int (consulted in September 2008).
Yu, L., Li-Hawkins, J., Hammer, R.E., Berge, K.E., Horton, J.D., Cohen, J.C., Hobbs, H.H. (2002): Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.J Clin Invest,110, 671–680.
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Sanclemente, T., Marques-Lopes, I., Puzo, J. et al. Role of naturally-occurring plant sterols on intestinal cholesterol absorption and plasmatic levels. J Physiol Biochem 65, 87–98 (2009). https://doi.org/10.1007/BF03165972
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DOI: https://doi.org/10.1007/BF03165972