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Impact of phytosterols on mitochondrial functions

Published online by Cambridge University Press:  20 April 2011

Gérard Lizard*
Affiliation:
Centre de Recherche INSERM 866, Lipids Nutrition Cancer, Equipe Biochimie Métabolique et Nutritionnelle, Faculté des Sciences Gabriel, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France email [email protected]
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Abstract

Type
Invited Commentary
Copyright
Copyright © The Author 2011

Phytosterols are structurally related to cholesterol and are mainly C28 and C29 carbon steroid alcohols(Reference Otaegui-Arrazola, Menendez-Carreno and Ansorena1). Plant sterols, also named phytosterols, are integral components of the membrane lipid bilayer of plant cells(Reference Schuler, Milon and Nakatani2). Unlike animal systems in which cholesterol is most often the single final product of sterol synthesis, each plant species has its own characteristic distribution of phytosterols, with the three most common phytosterols in nature being β-sitosterol, campesterol and stigmasterol(Reference Benveniste3). In addition to the free sterol form, phytosterols are also found in the form of conjugates, particularly fatty acyl sterol esters.

In humans, phytosterol absorption is considerably less than that of cholesterol(Reference Subbiah4). Some investigations support that phytosterols decrease cholesterol absorption, and thus reduce circulating concentrations of cholesterol(Reference Gupta, Guyomard and Zaman5). Indeed, in the intestine, phytosterols compete with cholesterol(Reference Calpe-Berdiel, Escolà-Gil and Blanco-Vaca6), leading to reduced cholesterol absorption and, as a consequence, to a lower plasma LDL-cholesterol concentration(Reference Malinowski and Gehret7). In addition, phytosterols appear not only to play an important role in the regulation of CVD but also to exhibit anti-cancer properties(Reference Jones and AbuMweis8, Reference Bradford and Awad9). The major currently identified and well-recognised side effects associated with the consumption of phytosterols are that they reduce the blood concentrations of fat-soluble vitamins, such as vitamins A, D, E and K(Reference Borel10, Reference Tikkanen11), and that they favour an increase in plasma phytostanols(Reference Calpe-Berdiel, Méndez-González and Blanco-Vaca12), resulting from phytosterol auto-oxidation(Reference Dutta, Savage, Guardiola, Dutta, Codony and Savage13, Reference Dutta, Guardiola, Dutta, Codony and Savage14), which have been described to trigger cell death on different cell types when used at elevated concentrations(Reference Tabas15Reference Lizard17). Based on their established and putative beneficial effects, plant sterols have been added to various food matrices, including juices, non-fat beverages, milk and yogurt, margarine, and cheese(Reference Abumweis and Jones18), which are among the most prominent examples of a set of foods designated as ‘functional foods’. The drawback of functional foods is that they can provide nutrients at levels above and beyond existing recommended intakes, and that they are inconsistent with the definition of physiological requirement(Reference Jones and Varady19). As relatively little is known about the effects of chronic consumption of functional foods enriched in phytosterols, their impact on cellular organelles, especially mitochondria and peroxisomes playing major roles in glucose and/or lipid metabolism(Reference Wanders and Waterham20, Reference Schrauwen, Schrauwen-Hinderling and Hoeks21), cannot be excluded and needs to be clarified.

Currently, whereas only a few data are available on the effects of phytosterols on mitochondria, a number of investigations have supported that this organelle can constitute a potential direct or indirect target of phytosterols. Thus, stigmasterol can alter the voltage-dependence of the voltage-dependent anion-selective channel purified from the mitochondria of bean seeds (Phaseolus coccineus)(Reference Mlayeh, Chatkaew and Léonetti22). However, on isolated brain mitochondria, stigmasterol and β-sitosterol had no effect on mitochondrial functions studied at concentrations up to 100 μmol/mg protein(Reference Panov, Kubalik and Brooks23). On the other hand, β-sitosterol favours an apoptotic mode of cell death associated with mitochondrial modifications, including a cytosolic release of cytochrome c in HT116 human colon cancer cells(Reference Choi, Kong and Kim24), and conferred a radioprotective effect on thymocytes by acting on the maintenance of mitochondrial membrane stability(Reference Li, Zhou and Lin25). At the mitochondrial level, some major enzymes involved in cholesterol transport and metabolism, such as the gonadal steroidogenic acute regulatory protein (StAR) and the hepatic mitochondrial sterol 27-hydroxylase (CYP27A1), participating in the degradation of cholesterol to bile acids can be altered by sitosterol(Reference Nguyen, Shefer and Salen26, Reference Sharpe, Woodhouse and Moon27). Thus, in vivo implants of β-sitosterol in male goldfish (Carassius auratus) not only cause reductions of reactive cholesterol pools in mitochondria isolated from gonads but also decrease the expression of gonadal StAR, a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones(Reference Sharpe, Woodhouse and Moon27, Reference Leusch and MacLatchy28). In addition, analysis of Lineweaver–Burk double reciprocal plots of sterol 27-hydroxylase activities on human liver extracts (where mitochondrial sterol 27-hydroxylase activities were measured with increasing concentrations of the cholesterol substrate, in the absence and presence of 100 and 300 μm-sitosterol) revealed that sitosterol inhibited mitochondrial sterol 27-hydroxylase activity up to 50 % by a competitive mechanism(Reference Nguyen, Shefer and Salen26). Moreover, the in vitro investigation by Danesi et al. (Reference Danesi, Ferioli and Fiorenza Caboni29), published in this issue of the British Journal of Nutrition, on supplemented rat cardiomyocytes with different concentrations of a phytosterol mixture (mainly containing sitosterol, campesterol and stigmasterol) within the range of plasma concentrations considered effective for cholesterol lowering(Reference Vanstone, Raeini-Sarjaz and Parsons30), clearly shows that phytosterols used in these conditions did not induce apoptosis, but rather favour a reduction in metabolic activity (measured as 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) conversion) and a slowing down of cell growth. The lower MTT conversion and the similar lactate dehydrogenase release suggest that phytosterols more efficiently target mitochondria than plasma membrane integrity, a possibility that cannot be excluded.

Thus, based on currently published data obtained by different laboratories, there is some evidence that mitochondria could be a potential direct or indirect target of phytosterols, and that these can trigger some mitochondrial dysfunctions even at concentrations considered effective for cholesterol lowering. Therefore, as mitochondria are a major cellular organelle involved in energy production, glucose and lipid metabolism, it is important to identify, in a metabolic context, the impact of phytosterols on this organelle in terms of ATP production and fatty acid β-oxidation, especially in subjects regularly eating and/or drinking ‘functional foods’ supplemented with phytosterols.

References

1 Otaegui-Arrazola, A, Menendez-Carreno, M, Ansorena, D, et al. (2010) Oxysterols: a world to explore. Food Chem Toxicol 48, 32893303.CrossRefGoogle ScholarPubMed
2 Schuler, I, Milon, A, Nakatani, Y, et al. (1991) Differential effects of plant sterols on water permeability and on acyl chain ordering of soybean phospatidylcholine bilayers. Proc Natl Acad Sci U S A 88, 69266930.CrossRefGoogle Scholar
3 Benveniste, P (2004) Biosynthesis and accumulation of sterols. Annu Rev Plant Biol 55, 429457.CrossRefGoogle ScholarPubMed
4 Subbiah, MT (1973) Dietary plant sterols: current status in human and animal sterol metabolism. Am J Clin Nutr 26, 219225.CrossRefGoogle ScholarPubMed
5 Gupta, A, Guyomard, V, Zaman, MJ, et al. (2010) Systematic review on evidence of the effectiveness of cholesterol-lowering drugs. Adv Ther 27, 348364.CrossRefGoogle ScholarPubMed
6 Calpe-Berdiel, L, Escolà-Gil, JC & Blanco-Vaca, F (2009) New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis 203, 1831.CrossRefGoogle ScholarPubMed
7 Malinowski, JM & Gehret, MM (2010) Phytosterols for dyslipidemia. Am J Health Syst Pharm 67, 11651173.CrossRefGoogle ScholarPubMed
8 Jones, PJ & AbuMweis, SS (2009) Phytosterols as functional food ingredients: linkages to cardiovascular disease and cancer. Curr Opin Clin Nutr Metab Care 12, 147151.CrossRefGoogle ScholarPubMed
9 Bradford, PG & Awad, AB (2010) Modulation of signal transduction in cancer cells by phytosterols. Biofactors 36, 241247.CrossRefGoogle ScholarPubMed
10 Borel, P (2003) Factors affecting intestinal absorption of highly lipophilic food microconstituents (fat-soluble vitamins, carotenoids and phytosterols). Clin Chem Lab Med 41, 979994.CrossRefGoogle ScholarPubMed
11 Tikkanen, MJ (2005) Plant sterols and stanols. Handb Exp Pharmacol 170, 215230.CrossRefGoogle Scholar
12 Calpe-Berdiel, L, Méndez-González, J, Blanco-Vaca, F, et al. (2009) Increased plasma levels of plant sterols and atherosclerosis: a controversial issue. Curr Atheroscler Rep 11, 391398.CrossRefGoogle ScholarPubMed
13 Dutta, PC & Savage, GP (2002) Formation and content of phytosterol oxidation products in food. In Cholesterol and Phytosterol Oxidation Products: Analysis, Occurrence, and Biological Effects, pp. 319334 [Guardiola, F, Dutta, PC, Codony, R and Savage, GP, editors]. Champaign, IL: AOCS Press.Google Scholar
14 Dutta, PC (2002) Determination of phytosterol oxidation producst in foods and biological samples. In Cholesterol and Phytosterol Oxidation Products: Analysis, Occurrence, and Biological Effects, pp. 335374 [Guardiola, F, Dutta, PC, Codony, R and Savage, GP, editors]. Champaign, IL: AOCS Press.Google Scholar
15 Tabas, I (2007) A two-carbon switch to sterol-induced autophagic death. Autophagy 3, 3841.CrossRefGoogle ScholarPubMed
16 Hovenkamp, E, Demonty, I, Plat, J, et al. (2008) Biological effects of oxidized phytosterols: a review of the current knowledge. Prog Lipid Res 47, 3749.CrossRefGoogle ScholarPubMed
17 Lizard, G (2008) Phytosterols: to be or not to be toxic; that is the question. Br J Nutr 100, 11501151.CrossRefGoogle ScholarPubMed
18 Abumweis, SS & Jones, PJ (2008) Cholesterol-lowering effect of plant sterols. Curr Atheroscler Rep 10, 467472.CrossRefGoogle ScholarPubMed
19 Jones, PJ & Varady, KA (2008) Are functional foods redefining nutritional requirements? Appl Physiol Nutr Metab 33, 118123.CrossRefGoogle ScholarPubMed
20 Wanders, RJ & Waterham, HR (2006) Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75, 295332.CrossRefGoogle ScholarPubMed
21 Schrauwen, P, Schrauwen-Hinderling, V, Hoeks, J, et al. (2010) Mitochondrial dysfunction and lipotoxicity. Biochim Biophys Acta 1801, 266271.CrossRefGoogle ScholarPubMed
22 Mlayeh, L, Chatkaew, S, Léonetti, M, et al. (2010) Modulation of plant mitochondrial VDAC by phytosterols. Biophys J 99, 20972106.CrossRefGoogle ScholarPubMed
23 Panov, A, Kubalik, N, Brooks, BR, et al. (2010) In vitro effects of cholesterol β-d-glucoside, cholesterol and cycad phytosterol glucosides on respiration and reactive oxygen species generation in brain mitochondria. J Membr Biol 237, 7177.CrossRefGoogle ScholarPubMed
24 Choi, YH, Kong, KR, Kim, YA, et al. (2003) Induction of Bax and activation of caspases during beta-sitosterol-mediated apoptosis in human colon cancer cells. Int J Oncol 23, 16571662.Google ScholarPubMed
25 Li, CR, Zhou, Z, Lin, RX, et al. (2007) Beta-sitosterol decreases irradiation-induced thymocyte early damage by regulation of the intracellular redox balance and maintenance of mitochondrial membrane stability. J Cell Biochem 102, 748758.CrossRefGoogle ScholarPubMed
26 Nguyen, LB, Shefer, S, Salen, G, et al. (1998) Competitive inhibition of hepatic sterol 27-hydroxylase by sitosterol: decreased activity in sitosterolemia. Proc Assoc Am Physicians 110, 3239.Google ScholarPubMed
27 Sharpe, RL, Woodhouse, A, Moon, TW, et al. (2007) Beta-sitosterol and 17beta-estradiol alter gonadal steroidogenic acute regulatory protein (StAR) expression in goldfish, Carassius auratus. Gen Comp Endocrinol 151, 3441.CrossRefGoogle ScholarPubMed
28 Leusch, FD & MacLatchy, DL (2003) In vivo implants of beta-sitosterol cause reductions of reactive cholesterol pools in mitochondria isolated from gonads of male goldfish (Carassius auratus). Gen Comp Endocrinol 134, 255263.CrossRefGoogle ScholarPubMed
29 Danesi, F, Ferioli, F, Fiorenza Caboni, M, et al. (2011) Phytosterol supplementation reduces metabolic activity and slows cell growth in cultured rat cardiomyocytes. Br J Nutr 106, 540548.CrossRefGoogle ScholarPubMed
30 Vanstone, CA, Raeini-Sarjaz, M, Parsons, WE, et al. (2002) Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons. Am J Clin Nutr 76, 12721278.CrossRefGoogle ScholarPubMed