The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism
Abstract
:1. Introduction
2. Phytosterols Chemistry and Dietary Sources
3. Bioavailability of Phytosterols
4. Cholesterol-Lowering Effect of Phytosterols in Patients with Hypercholesterolemia-Related Diseases
5. The Underlying Mechanism of Phytosterols in Regulating Cholesterol Homeostasis
5.1. Phytosterols Regulate the Absorption of Cholesterol in the Gut
5.2. Phytosterols Regulate Liver Cholesterol Metabolism
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Cabral, C.E.; Klein, M.R.S.T. Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases. Arq. Bras. Cardiol. 2017, 109, 475–482. [Google Scholar] [CrossRef] [PubMed]
- Jiménez-Escrig, A.; Santos-Hidalgo, A.B.; Saura-Calixto, F. Common Sources and Estimated Intake of Plant Sterols in the Spanish Diet. J. Agric. Food Chem. 2006, 54, 3462–3471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martianto, D.; Bararah, A.; Andarwulan, N.; Średnicka-Tober, D. Cross-Sectional Study of Plant Sterols Intake as a Basis for Designing Appropriate Plant Sterol-Enriched Food in Indonesia. Nutrients 2021, 13, 452. [Google Scholar] [CrossRef] [PubMed]
- Witkowska, A.M.; Waśkiewicz, A.; Zujko, M.E.; Mirończuk-Chodakowska, I.; Cicha-Mikołajczyk, A.; Drygas, W. Assessment of Plant Sterols in the Diet of Adult Polish Population with the Use of a Newly Developed Database. Nutrients 2021, 13, 2722. [Google Scholar] [CrossRef]
- Lesma, G.; Luraghi, A.; Bavaro, T.; Bortolozzi, R.; Rainoldi, G.; Roda, G.; Viola, G.; Ubiali, D.; Silvani, A. Phytosterol and γ-Oryzanol Conjugates: Synthesis and Evaluation of their Antioxidant, Antiproliferative, and Anticholesterol Activities. J. Nat. Prod. 2018, 81, 2212–2221. [Google Scholar] [CrossRef]
- Vilahur, G.; Ben-Aicha, S.; Diaz-Riera, E.; Badimon, L.; Padró, T. Phytosterols and Inflammation. Curr. Med. Chem. 2019, 26, 6724–6734. [Google Scholar] [CrossRef]
- Qasimi, M.I.; Nagaoka, K.; Watanabe, G. The Effects of Phytosterols on the Sexual Behavior and Reproductive Function in the Japanese Quail (Coturnix Coturnix Japonica). Poult. Sci. 2017, 96, 3436–3444. [Google Scholar] [CrossRef]
- Ostlund, R.E.; Racette, S.B.; Okeke, A.; Stenson, W.F. Phytosterols that Are Naturally Present in Commercial Corn Oil Significantly Reduce Cholesterol Absorption in Humans. Am. J. Clin. Nutr. 2002, 75, 1000–1004. [Google Scholar] [CrossRef]
- Normén, L.; Dutta, P.; Lia, A.; Andersson, H. Soy Sterol Esters and Beta-Sitostanol Ester as Inhibitors of Cholesterol Absorption in Human Small Bowel. Am. J. Clin. Nutr. 2000, 71, 908–913. [Google Scholar] [CrossRef] [Green Version]
- Agren, J.J.; Tvrzicka, E.; Nenonen, M.T.; Helve, T.; Hänninen, O. Divergent Changes in Serum Sterols during a Strict Uncooked Vegan Diet in Patients with Rheumatoid Arthritis. Br. J. Nutr. 2001, 85, 137–139. [Google Scholar] [CrossRef] [Green Version]
- Li, Q.; ** Type 2 Diabetes; a Randomized, Double-Blind, Placebo-Controlled Study. Nutr. Diabetes 2018, 8, 30. [Google Scholar] [CrossRef] [Green Version]
- Alvarez-Sala, A.; Blanco-Morales, V.; Cilla, A.; Silvestre, R.Á.; Hernández-Álvarez, E.; Granado-Lorencio, F.; Barberá, R.; Garcia-Llatas, G. A Positive Impact on the Serum Lipid Profile and Cytokines after the Consumption of a Plant Sterol-Enriched Beverage with a Milk Fat Globule Membrane: A Clinical Study. Food Funct. 2018, 9, 5209–5219. [Google Scholar] [CrossRef]
- Cheung, C.-L.; Ho, D.K.-C.; Sing, C.-W.; Tsoi, M.-F.; Cheng, V.K.-F.; Lee, G.K.-Y.; Ho, Y.-N.; Cheung, B.M.Y. Randomized Controlled Trial of the Effect of Phytosterols-Enriched Low-Fat Milk on Lipid Profile in Chinese. Sci. Rep. 2017, 7, 41084. [Google Scholar] [CrossRef] [Green Version]
- Duan, L.-P.; Wang, H.H.; Wang, D.Q.H. Cholesterol Absorption Is Mainly Regulated by the Jejunal and Ileal ATP-Binding Cassette Sterol Efflux Transporters Abcg5 and Abcg8 in Mice. J. Lipid Res. 2004, 45, 1312–1323. [Google Scholar] [CrossRef] [Green Version]
- Reeskamp, L.F.; Volta, A.; Zuurbier, L.; Defesche, J.C.; Hovingh, G.K.; Grefhorst, A. ABCG5 and ABCG8 Genetic Variants in Familial Hypercholesterolemia. J. Clin. Lipidol. 2020, 14, 207–217. [Google Scholar] [CrossRef]
- Moreau, R.A.; Nystrom, L.; Whitaker, B.D.; Winkler-Moser, J.K.; Baer, D.J.; Gebauer, S.K.; Hicks, K.B. Phytosterols and their Derivatives: Structural Diversity, Distribution, Metabolism, Analysis, and Health-Promoting Uses. Prog. Lipid Res. 2018, 70, 35–61. [Google Scholar] [CrossRef]
- Davis, H.R., Jr.; Zhu, L.J.; Hoos, L.M.; Tetzloff, G.; Maguire, M.; Liu, J.; Yao, X.; Iyer, S.P.; Lam, M.H.; Lund, E.G.; et al. Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-Body Cholesterol Homeostasis. J. Biol. Chem. 2004, 279, 33586–33592. [Google Scholar] [CrossRef] [Green Version]
- Altmann, S.W.; Davis, H.R., Jr.; Zhu, L.J.; Yao, X.; Hoos, L.M.; Tetzloff, G.; Iyer, S.P.; Maguire, M.; Golovko, A.; Zeng, M.; et al. Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 2004, 303, 1201–1204. [Google Scholar] [CrossRef] [Green Version]
- Mattson, F.H.; Grundy, S.M.; Crouse, J.R. Optimizing the Effect of Plant Sterols on Cholesterol Absorption in Man. Am. J. Clin. Nutr. 1982, 35, 697–700. [Google Scholar] [CrossRef]
- Plat, J.; Mensink, R.P. Plant Stanol and Sterol Esters in the Control of Blood Cholesterol Levels: Mechanism and Safety Aspects. Am. J. Cardiol. 2005, 96, 15D–22D. [Google Scholar] [CrossRef]
- Cedó, L.; Farràs, M.; Lee-Rueckert, M.; Escolà-Gil, J.C. Molecular Insights into the Mechanisms Underlying the Cholesterol- Lowering Effects of Phytosterols. Curr. Med. Chem. 2019, 26, 6704–6723. [Google Scholar] [CrossRef]
- Doornbos, A.M.E.; Meynen, E.M.; Duchateau, G.S.M.J.E.; van der Knaap, H.C.M.; Trautwein, E.A. Intake Occasion Affects the Serum Cholesterol Lowering of a Plant Sterol-Enriched Single-Dose Yoghurt Drink in Mildly Hypercholesterolaemic Subjects. Eur. J. Clin. Nutr. 2006, 60, 325–333. [Google Scholar] [CrossRef]
- Yang, J.-W.; Ji, H.-F. Phytosterols as Bioactive Food Components against Nonalcoholic Fatty Liver Disease. Crit. Rev. Food Sci. Nutr. 2021, 1–12. [Google Scholar] [CrossRef]
- Reeskamp, L.F.; Meessen, E.C.E.; Groen, A.K. Transintestinal Cholesterol Excretion in Humans. Curr. Opin. Lipidol. 2018, 29, 10–17. [Google Scholar] [CrossRef] [Green Version]
- Jakulj, L.; van Dijk, T.H.; de Boer, J.F.; Kootte, R.S.; Schonewille, M.; Paalvast, Y.; Boer, T.; Bloks, V.W.; Boverhof, R.; Nieuwdorp, M.; et al. Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion. Cell Metab. 2016, 24, 783–794. [Google Scholar] [CrossRef] [Green Version]
- Nakano, T.; Inoue, I.; Takenaka, Y.; Ikegami, Y.; Kotani, N.; Shimada, A.; Noda, M.; Murakoshi, T. Luminal Plant Sterol Promotes Brush Border Membrane-to-Lumen Cholesterol Efflux in the Small Intestine. J. Clin. Biochem. Nutr. 2018, 63, 102–105. [Google Scholar] [CrossRef] [Green Version]
- Lifsey, H.C.; Kaur, R.; Thompson, B.H.; Bennett, L.; Temel, R.E.; Graf, G.A. Stigmasterol Stimulates Transintestinal Cholesterol Excretion Independent of Liver X Receptor Activation in the Small Intestine. J. Nutr. Biochem. 2020, 76, 108263. [Google Scholar] [CrossRef]
- Nakano, T.; Inoue, I.; Murakoshi, T. A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Reappraises How Plant Sterol Intake Reduces Circulating Cholesterol Levels. Nutrients 2019, 11, 310. [Google Scholar] [CrossRef] [Green Version]
- Field, F.J.; Born, E.; Mathur, S.N. Stanol Esters Decrease Plasma Cholesterol Independently of Intestinal ABC Sterol Transporters and Niemann-Pick C1-like 1 Protein Gene Expression. J. Lipid Res. 2004, 45, 2252–2259. [Google Scholar] [CrossRef] [Green Version]
- Juritsch, A.; Tsai, Y.-T.; Patel, M.S.; Rideout, T.C. Transcriptional Control of Enterohepatic Lipid Regulatory Targets in Response to Early Cholesterol and Phytosterol Exposure in ApoE Mice. BMC Res. Notes 2017, 10, 529. [Google Scholar] [CrossRef] [Green Version]
- Temel, R.E.; Gebre, A.K.; Parks, J.S.; Rudel, L.L. Compared with Acyl-CoA:Cholesterol O-Acyltransferase (ACAT) 1 and Lecithin:cholesterol Acyltransferase, ACAT2 Displays the Greatest Capacity to Differentiate Cholesterol from Sitosterol. J. Biol. Chem. 2003, 278, 47594–47601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liang, Y.T.; Wong, W.T.; Guan, L.; Tian, X.Y.; Ma, K.Y.; Huang, Y.; Chen, Z.-Y. Effect of Phytosterols and their Oxidation Products on Lipoprotein Profiles and Vascular Function in Hamster Fed a High Cholesterol Diet. Atherosclerosis 2011, 219, 124–133. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.; Ren, F.; Wei, H.; Liu, L.; Shen, T.; Xu, S.; Wei, J.; Ren, J.; Ni, H. Combination of Berberine and Evodiamine Inhibits Intestinal Cholesterol Absorption in High Fat Diet Induced Hyperlipidemic Rats. Lipids Health Dis. 2017, 16, 239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Field, F.J.; Born, E.; Mathur, S.N. Effect of Micellar Beta-Sitosterol on Cholesterol Metabolism in CaCo-2 Cells. J. Lipid Res. 1997, 38, 348–360. [Google Scholar] [CrossRef]
- Batta, A.K.; Xu, G.; Honda, A.; Miyazaki, T.; Salen, G. Stigmasterol Reduces Plasma Cholesterol Levels and Inhibits Hepatic Synthesis and Intestinal Absorption in the Rat. Metabolism 2006, 55, 292–299. [Google Scholar] [CrossRef]
- Plat, J.; Mensink, R.P. 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. 2002, 16, 258–260. [Google Scholar] [CrossRef]
- Cohn, J.S.; Kamili, A.; Wat, E.; Chung, R.W.S.; Tandy, S. Reduction in Intestinal Cholesterol Absorption by Various Food Components: Mechanisms and Implications. Atheroscler. Suppl. 2010, 11, 45–48. [Google Scholar] [CrossRef]
- Demonty, I.; Ras, R.T.; van der Knaap, H.C.M.; Duchateau, G.S.M.J.E.; Meijer, L.; Zock, P.L.; Geleijnse, J.M.; Trautwein, E.A. Continuous Dose-Response Relationship of the LDL-Cholesterol-Lowering Effect of Phytosterol Intake. J. Nutr. 2009, 139, 271–284. [Google Scholar] [CrossRef] [Green Version]
- Ottestad, I.; Ose, L.; Wennersberg, M.H.; Granlund, L.; Kirkhus, B.; Retterstøl, K. Phytosterol Capsules and Serum Cholesterol in Hypercholesterolemia: A Randomized Controlled Trial. Atherosclerosis 2013, 228, 421–425. [Google Scholar] [CrossRef]
- He, W.-S.; Wang, M.-G.; Pan, X.-X.; Li, J.-J.; Jia, C.-S.; Zhang, X.-M.; Feng, B. Role of Plant Stanol Derivatives in the Modulation of Cholesterol Metabolism and Liver Gene Expression in Mice. Food Chem. 2013, 140, 9–16. [Google Scholar] [CrossRef]
- Cedó, L.; Santos, D.; Ludwig, I.A.; Silvennoinen, R.; García-León, A.; Kaipiainen, L.; Carbó, J.M.; Valledor, A.F.; Gylling, H.; Motilva, M.-J.; et al. Phytosterol-Mediated Inhibition of Intestinal Cholesterol Absorption in Mice Is Independent of Liver X Receptor. Mol. Nutr. Food Res. 2017, 61, 201700055. [Google Scholar] [CrossRef]
- Méndez-González, J.; Süren-Castillo, S.; Calpe-Berdiel, L.; Rotllan, N.; Vázquez-Carrera, M.; Escolà-Gil, J.C.; Blanco-Vaca, F. Disodium Ascorbyl Phytostanol Phosphate (FM-VP4), a Modified Phytostanol, Is a Highly Active Hypocholesterolaemic Agent that Affects the Enterohepatic Circulation of Both Cholesterol and Bile Acids in Mice. Br. J. Nutr. 2010, 103, 153–160. [Google Scholar] [CrossRef] [Green Version]
Study Population | Length of Intervention (Weeks) | Adjustments Considered | The Main Results of Phytosterol Intervention | References |
---|---|---|---|---|
Healthy individuals with slightly higher TG levels (≥1.4 mmol/L) and LDL-C concentrations (≥3.4 mmol/L) (n = 260) | 4 | TG, LDL-C, TC, | Participants in the intervention group had significantly lower concentrations of TC (3.9%), TG (10.6%), and LDL-C (5.2%) | [68] |
Patients with metabolic syndrome (n = 108) | 8 | TC, LDL-C, sdLDL, TG | Patients in the intervention group had significantly lower concentrations of TC (15.9%), TG (19.1%), LDL-C (20.3%), and sdLDL (p < 0.05) | [69] |
Normocholesterolemic participants (n = 159) | 3 | LDL-C | The concentration of LDL-C (5.96%, p = 0.028) was significantly lower in patients in the intervention group | [42] |
The fasting TC concentration of the participants was 6.57 ± 0.13 mmol/L (n = 70) | 4 | TC, LDL-C | Patients in the intervention group had significantly lower concentrations of TC (4.8%, p < 0.05) and LDL-C (8.1%, p < 0.05) | [70] |
Healthy individuals at increased risk of T2DM and patients with T2DM (n = 161) | 6 | TC, LDL-C, TG | Individuals in the phytosterol intervention group had significantly lower fasting TC (4.2%), TG (8.3%), and LDL-C (4.6%) concentrations | [71] |
Postmenopausal women (n = 38) | 6 | TC, LDL-C | Serum TC (212.9 ± 25.8 mg/dL) and LDL-C concentrations (121.7 ± 24.4 mg/dL) decreased significantly after phytosterol treatment compared to previous (220.0 ± 27.8 mg/dL) (129.4 ± 28.5 mg/dL) | [72] |
Individuals not taking cholesterol-lowering drugs or without diabetes (n = 221) | 3 | TC, LDL-C, diastolic blood pressure | Serum LDL-C concentration (9.5 ± 2%), TC (p < 0.01), and diastolic blood pressure (p = 0.01) were significantly reduced after phytosterol intervention | [73] |
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Li, X.; **n, Y.; Mo, Y.; Marozik, P.; He, T.; Guo, H. The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism. Molecules 2022, 27, 523. https://doi.org/10.3390/molecules27020523
Li X, **n Y, Mo Y, Marozik P, He T, Guo H. The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism. Molecules. 2022; 27(2):523. https://doi.org/10.3390/molecules27020523
Chicago/Turabian StyleLi, ** He, and Honghui Guo. 2022. "The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism" Molecules 27, no. 2: 523. https://doi.org/10.3390/molecules27020523