Therapeutic potential and safety of phytosterols in contemporary clinical practice

Abstract

Phytosterols (PS) are plant-derived compounds that reduce intestinal cholesterol absorption. They are found in natural products, such as vegetable oils, vegetables, fruits, nuts, grains, and legumes. PS play a role as an adjunct to the pharmacological treatment of dyslipidemia, especially in high-risk patients who fail to achieve target levels of low-density lipoprotein cholesterol (LDL-C) or are intolerant to standard therapies, such as statins. This review aimed to summarize current knowledge on the mechanism of action of PS, their clinical efficacy and clinical applications, safety profile, gaps in knowledge on PS, and clinically relevant information on PS use in daily practice.

According to the available literature, PS lower the levels of total cholesterol, LDL-C, triglycerides, intermediate-density B cholesterol, and apolipoprotein B, while increasing the level of high-density lipoprotein cholesterol. Additionally, they exhibit anti-inflammatory and antioxidant properties. They are commonly referred to as safe and well-tolerated dietary supplements, although there are concerns regarding their impact on phytosterolemia and fat-soluble vitamin absorption. Current studies focus on the enhancement of PS bioavailability by esterification and nanodelivery systems, as well as the potential anticancer properties of PS. There are gaps in knowledge regarding PS long-term safety, genetic factors affecting their effect on various lipid fractions, the effect of intestinal microbiome on PS efficacy, and PS interactions with other cholesterol-lowering drugs.

Introduction

Phytosterols (PS) are plant-derived compounds whose structure is similar to that of cholesterol (CHOL). Consequently, they decrease intestinal absorbtion of CHOL, leading to an improved lipid profile. Main PS are sitosterol, campesterol, and sigmasterol. They are found in vegetable oils and, to a lesser extent, in vegetables, fresh fruits, nuts, grains, and legumes.¹ Dietary intake is the only source of PS, since they are not synthesized within human body and do not have any physiological functions.² Due to the widespread presence of PS in foods and supplements, PS have become an adjunct to the pharmacological treatment of dyslipidemia, especially in very-high-risk patients who fail to achieve low-density lipoprotein cholesterol (LDL-C) target levels with guideline-recommended therapy or in individuals intolerant to first-line therapies. Several studies also demonstrated anti-inflammatory and antioxidant effects of PS. However, their long-term efficacy and optimal integration into the guideline-recommended treatment remain unclear.³ There are various recent studies focusing on the mechanisms of action of PS, their potential use in medical practice, as well as the risks and controversies associated with them.^4-6

This aim of this review was to summarize latest knowledge on the mechanism of action of PS, their clinical efficacy and current clinical applications, PS safety profile, the gaps in knowledge on PS, and indications for PS use in daily practice.

Mechanism of action

The mechanism of action of PS comprises various elements. They have impact on CHOL absorption, influence CHOL biliary excretion and atherosclerotic plaque formation, and have antioxidant and anti-inflammatory properties.

CHOL and PS are absorbed in the small intestine in the form of micelles. They are transported inside the enterocytes via the Niemann–Pick C1-like intracellular cholesterol transporter 1 (NPC1L1) (Figure 1). However, about 98% of the initial PS and 40%–50% of CHOL are transported back into the intestinal lumen through the action of the ATP-binding cassette subfamily G member 5 (ABCG5)/ATP-binding cassette subfamily G member 8 (ABCG8) transport system. Eventually, approximately 50%–60% of CHOL and only 0.5%–2% of PS are absorbed into the body (Figure 2).^4,5

**Figure 1**. Phytosterol and cholesterol metabolism
Abbreviations: Apo-A, apolipoprotein A; ABCG5/8, adenosine triphosphate-binding cassette subfamily G member 5 / member 8; CHOL, cholesterol; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; NPC1L1, Niemann–Pick C1-like intracellular cholesterol transporter 1; PS, phytosterols; VLDL, very low-density lipoprotein

**Figure 2**. Influence of phytosterols on cholesterol absorption; A – absorption of cholesterol without phytosterols; B – absorption of cholesterol with phytosterols
Abbreviations: see Figure 1

Prior to their release into the lymphatic system, esterified CHOL and PS are encapsulated into chylomicrons, which are converted into remnants and transported to the liver. A small amount of free CHOL and sterols can be released from enterocytes via high-density lipoprotein (HDL) particles.

The liver is a reservoir of CHOL, both endogenously synthesized and derived from dietary sources. Also, the liver produces very low-density lipoprotein (VLDL), which contains triglycerides, CHOL, and apolipoprotein (Apo) B100. Subsequently, VLDL is transformed into intermediate-density lipoprotein (IDL), and finally into LDL, the principal transporter of CHOL in the bloodstream.^4,5 Part of CHOL in the liver is metabolized into bile acids and transported into the bile.

Plant sterols upregulate bile acid synthesis, escalating CHOL transport through the excretory biliary pathway. Also, they downregulate microsomal triglyceride transfer protein, which results in a decreased secretion of VLDL.⁶

CHOL can deposit in arterial walls, increasing the risk of cardiovascular events. Chylomicron remnants can also play a role in the creation of atherosclerotic plaques in arterial walls, which can lead to the development of cardiovascular diseases.^4,5 PS can accumulate in arterial walls; however, their absorption is minimal (2%), and their role in lowering total cholesterol (TC) level contributes to atherosclerosis prevention rather than atherosclerotic plaque formation.⁴

PS also reduce the levels of free radicals, such as hydroperoxides and hydrogen peroxide.^6,7 They activate catalase, superoxide dismutase, and glutathione, which exhibit antioxidant properties.^6,8,9 Additionally, PS inhibit lipid peroxidation and suppress proinflammatory cytokines.^10-14

PS play a crucial role in modulating CHOL metabolism. They not only lower CHOL absorption due to similar structure, but also influence CHOL biliary excretion and lipoprotein secretion. Moreover, they exhibit antioxidant and anti-inflammatory properties.

Clinical efficacy

According to the guidelines of leading scientific societies, such as the European Society of Cardiology (ESC) and European Atherosclerois Society (EAS), statins are the recommended first-line treatment for dyslipidemia, while ezetimibe is considered a second-line option. However, in some patients, especially those who cannot tolerate statins, PS play a role as an adjunct to the pharmacological treatment. The selection of the right dose and the effectiveness of PS in lowering TC, different lipoproteins, and triglycerides levels have been researched in a number of studies.^1,4,15-21

Based on the ESC/EAS guidelines, a daily intake of 2 g of PS can reduce LDL-C and TC levels by 7%–10%, while moderate-intensity statin therapy reduces LDL-C by 30%–50%.¹ A meta-analysis including 1777 patients treated with PS for 3–85 weeks confirmed the LDL-C–lowering effect of PS (median, –0.38 mmol/l; 95% CI, –0.5 to −0.27). It also showed that PS lowered Apo-B levels (median, 0.04 g/l; 95% CI, –0.06 to −0.02).¹⁶ A PS dose both below 2 g and above 2 g can increase HDL-C levels by about 0.04 mmol/l (95% CI, 0.01–0.06) (Figure 3), with 3 g of PS being the most effective dose to decrease TC and LDL-C levels.^16,17 The effect of doses greater than 4 g per day remains unclear.

**Figure 3**. Influence of phytosterols on lipid profile
Abbreviations: IDL-B, intermediate-density lipoprotein B; LDL-C, low-density lipoprotein cholesterol; others, see Figure 1

Another prospective study including 23 patients observed for 24 weeks also demonstrated that PS could lower IDL-B levels.¹⁸ A meta-analysis of 17 studies and 23 study arms demonstrated its triglyceride-lowering effect. It was reported that consumption of doses lower than or equal to 2 g of PS per day over 8 weeks lowered serum triglycerides by –3.77 mg/dl (95% CI, –6.04 to –1.51).⁴ Moreover, a randomized, double-blind, placebo-controlled clinical trial including 202 patients with metabolic syndrome showed a 15%–17% reduction in triglyceride levels in individuals taking 2 g of free-PS nanoparticles for 6 months, when compared with a placebo.¹⁹ Rideout et al²⁰ reported that hypertriglyceridemic individuals (>1.7 mmol/l) exhibited a greater triglyceride-lowering response to PS (11%–28%) than individuals with normal plasma triglyceride concentrations (0.8%–7%).

Interestingly, a randomized controlled trial including 41 patients showed that beside the dose, the efficacy of CHOL-lowering properties of PS depended on the administration route.²¹ PS added to fat-based food caused a reduction of the LDL-C level, as opposed to PS delivered in the form of softgel capsules.

Generally, PS demonstrate a TC-lowering effect. Their role in decreasing triglycerides and different lipoprotein levels has also been demonstrated. However, the optimal dosage in different populations and the long-term effect on lipid fractions remain unclear.

Current clinical applications

PS play a role in clinical practice due to their properties. They are natural, easily accessible, and effective in lowering TC and LDL-C levels, especially in patients who cannot take statins and fail to achieve LDL-C target levels or individuals with familial hypercholesterolemia.

PS are naturally present in plant-based foods, such as margarine, bread, cereal, fruits, and vegetables.²² There are also foods enriched in PS, for instance, fresh dairy products, condiment sauces, soy, fruit drinks, and sausages. Another source of PS are standalone dietary supplements. They are most effective when used alongside lifestyle modifications, such as a healthy diet.^1,16,18 The intake of products enriched with PS in amounts ranging from 1.5 to 2.4 g per day has been shown to reduce TC and LDL-C levels by approximately 10% over a period of a few weeks to 1 or 2 years.²³ Table 1 presents examples of doses, methods, and duration of PS administration in the conducted studies.

**Table 1**. Dosing and administration of phytosterols
Trial	Dosage	Food product	Duration
Ruiu et al⁵⁸	1 g/d	Fermented pasteurized milk	4 weeks
Amir Shaghaghi et al⁵⁹	2 g/d	Yogurt	4 weeks
Castro Cabezas et al⁶⁰	3 g/d	Margarine	6 weeks
Sialvera et al⁶¹	4 g/d	Yogurt	2 months

According to the ESC/EAS and the Polish Lipid Society guidelines, PS dose higher than 2 g per day taken with the main meal may be considered in the following situations: 1) in patients with high CHOL levels at an intermediate or low global cardiovascular risk who do not yet qualify for pharmacotherapy; 2) as a supplement to pharmacological therapy in high-and very-high-risk patients who fail to reach their target LDL-C levels with statins or cannot be treated with statins; and 3) in patients with familial hypercholesterolemia (aged >6 years).^1,15 Statin therapy can be associated with adverse effects, such as myopathy, myalgia, rhabdomyolysis, hepatotoxicity, and diabetes mellitus, occurring more likely in elderly patients. This prompts both physicians and patients to search for alternative therapies.^24,25 Moreover, PS use in high-risk populations, such as individuals with familial hypercholesterolemia, highlights their potential as a complementary therapy.^26,27

In conclusion, PS present in natural products or obtained via supplementation may be particularly useful in individuals who do not tolerate statins or require additional lipid-lowering strategies. Their integration into a healthy diet combined with lifestyle modifications represents a useful method in the management of hypercholesterolemia.

Safety profile

PS are commonly referred to as safe and well-tolerated dietary supplements. Their adverse effects are generally mild and include nausea, diarrhea, constipation, and indigestion.²⁸ However, the risk of adverse effects may be higher in patients with phytosterolemia. Moreover, PS can impair β-carotene and vitamin D absorption.

Phytosterolemia, also known as sitosterolemia, is a rare metabolic disorder inherited in an autosomal-recessive manner, usually manifesting in early childhood. Worldwide, only around 100 cases have been reported in literature. Phytosterolemia is caused by mutations in the genes responsible for encoding the ABCG5/8 cotransporter, which is responsible for pumping sterols back into the small intestine lumen and their transport from hepatocytes into the bile ducts. This leads to intestinal hyperabsorption and reduced biliary excretion of dietary sterols. Furthermore, individuals with phytosterolemia exhibit elevated CHOL biosynthesis due to the increased 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, which can result in hypercholesterolemia and atherosclerosis. While concentrations of PS in healthy individuals vary between 0.5 and 2 mg/dl, patients with phytosterolemia can reach concentrations of up to 3 mg/dl in heterozygotes and up to 65 mg/dl in homozygotes.^29,30 Some studies reported that those patients can exhibit increased cardiovascular risk; however, it is still debatable whether this is due to increased PS levels or increased LDL-C levels.²⁹

Elevated PS levels have been shown to promote atherosclerosis in some animal models.^29,31 Nevertheless, human studies have not consistently supported these findings.²⁹ There is no apparent evidence that the elevation in plasma PS concentrations of up to 15 mg/dl, induced by the consumption of PS-enriched foods, might cause atherogenic effects that could surpass the 20–40 times greater reduction in LDL-C levels. However, another study reported that in 30% of the participants, consumption of PS-enriched foods did not cause a drop in LDL-C levels, which may indicate the influence of genetic factors on PS activity.³ In homozygous familial phytosterolemia, atherosclerosis seems to be caused by excessively high plasma LDL-C levels (770 mg/dl) starting in childhood, and not by high PS levels.

Several experiments demonstrated an impaired absorption of β-carotene and vitamin D in the presence of PS.^30,32 However, PS did not affect the absorption of vitamins A and K.³⁰

Hence, while PS present potential benefits, their effect depends on other factors, such as genetics and dosage. Their safety, especially in patients with disorders such as phytosterolemia, is not fully understood.

Future perspectives in clinical practice

Research on PS is constantly developing and the possibilities for their use in clinical practice are expanding. Advancements in food technology and chemical and physical modifications of PS aim to enhance their limited bioavailability and susceptibility to degradation.^33-38 Moreover, potential anticancer properties of PS have been reported in recent studies.^39-43

The bioavailability of PS within dietary matrices is limited, as they are susceptible to oxidative degradation and exhibit diminished solubility in aqueous environments. Nonetheless, many technological strategies have been formulated to improve PS incorporation into food products, which could guarantee sufficient quantities to effectively lower CHOL levels.³³ The variety of molecular structures of PS can have an impact on their bioavailability and physicochemical features. These structures can be free sterols, sterol esters, steryl glycosides, and acylated glycosides.^34,35 Previous studies indicated that PS bioavailability can be increased through both chemical and physical modifications.^36,37 Chemical modifications focused on esterification to increase oil and water solubility, while physical modifications involved microenocapsulation. Development of a nanoscale delivery system can contribute to the improvement in absorption and reduced loss of biologically active substances.³⁶ Currently, research is focusing on the influence of the food matrix on nanodelivery systems and the impact of food processing on PS bioavailability. Also, researchers aim to find the way to produce the most stable nanocapsules to deliver PS.³⁸ Oxidates which can be produced during PS ester synthesis have shown toxicity in several studies. The toxicity of nanocarriers remains unclear.³⁶

Recent studies have reported the potential anticancer effects of PS. They may decrease the risk of breast,³⁹ ovary,⁴⁰ lung, liver,⁴¹ stomach,⁴² esophageal,⁴³ and colorectal cancer development.⁴⁴ PS protective mechanisms of action against cancer are not clear, but several potential pathways have been proposed. These include suppressing carcinogen production, hindering the growth and proliferation of cancer cells, preventing invasion and metastasis, and triggering cell cycle arrest and apoptosis. Additional mechanisms suggested in animal models involve reducing angiogenesis, limiting cancer cell adhesion and invasion, and decreasing the production of reactive oxygen species.^41,45

The existing research indicates the growing role of PS in clinical practice (Tables 2 and 3). Their potential anticancer effects and innovative technologies to enhance their bioavailability are being intensively studied. However, further research, especially human studies, is required to fully assess their efficacy and safety.

**Table 2**. Effects of phytosterols on different health conditions
Parameter	Effect of phytosterols	Reference
Lipid-lowering properties	Reduction of LDL-C, TC, Apo-B, IDL-B, and triglycerides levels	^{1,4,16,17,18,19}
Cardiovascular risk	Lowering the risk of atherosclerotic plaque formation in arterial walls by reducing LDL-C and TC levels Possible increased risk of PS adverse effects in patients with phytosterolemia Increased cardiovascular risk in individuals with phytosterolemia (debated)	^4,5,29,30,31
Anti-inflammatory and antioxidant properties	Decreasing proinflammatory cytokines Reduction of oxidative stress Inhibition of lipid peroxidation	^{6,9,10,11,12,13,14}
Cancer prevention	Possible anticancer properties (eg, breast, colorectal, liver, stomach, and esophageal cancer)	^{39,40,41,42,43}
Impact on gut microbiome	Modification of microbiome composition Increasing short-chain fatty acids production Impact on expression of genes related to cholesterol metabolism	^{48,49,50,51,52}
Abbreviations: TC, total cholesterol; others, see Figure 1

**Table 3**. Advantages and disadvantages of phytosterols
Advantages	Disadvantages
Reduction of intestinal cholesterol absorption due to similar structure¹ Reduction of the levels of free radicals, such as hydroperoxides and hydrogen peroxide^6,7 Antioxidant properties^6,9 Lowering TC and triglyceride levels^4,16,17,19 Lowering LDL-C, IDL-B, and Apo-B levels^16,17,18 Increasing HDL-C level^16,17 Useful in individuals who do not tolerate statins or require additional lipid-lowering strategies¹ Found in natural products¹	Increased risk of adverse effects in patients with phytosterolemia^29,30 Potential impaired absorption of β-carotene and vitamin D^30,32 Limited bioavailability within dietary matrices due to susceptibility to oxidative degradation and diminished solubility in aqueous environments³³ Unclear long-term efficacy and optimal integration into the guideline-recommended treatment¹⁶
Abbreviations: HDL-C, high-density lipoprotein cholesterol; others see Figures 1 and 3

Gaps in knowledge and research directions

Current research underlines several gaps in knowledge concerning PS long-term safety and the effect of gut microbiome and genetics on their efficacy. PS interactions with other CHOL-lowering drugs are not fully understood either.

Only a few studies analyzed PS treatment lasting over 3 months. Hence, PS long-term efficacy and safety remain unclear.¹⁶ The impact of possible increase in plasma PS levels on cardiovascular risk is also unknown.^3,24 There is no evidence indicating that the consumption of plant sterols and stanols affects markers of atherosclerosis, such as carotid intima-media thickness and flow-mediated dilation.^24,46

Recent studies have indicated the influence of genetics and the gut microbiome on CHOL absorption.^4,47,48 Thus, these factors may also affect the effectiveness of PS and the selection of personalized treatment.

Loss-of-function (LoF) variants in genes encoding intestinal transporters, such as NPC1L1 and ABCG5/G8 transporters, have demonstrated associations between CHOL metabolism and atherosclerotic cardiovascular diseases. Specifically, LoF variants in NPC1L1 lead to decreased CHOL absorption, while those in ABCG5 and ABCG8 result in increased CHOL absorption.^4,47

There is a growing number of studies highlighting the bidirectional interaction between PS and the gut microbiome. The gut microbiota can influence CHOL metabolism. It can ferment dietary fiber to produce short-chain fatty acids (SCFAs), which can inhibit CHOL synthesis.^48,49 It can convert CHOL to coprostanol, which is characterized by a very low absorption rate.^48,50 Also, it can affect the expression of some genes related to CHOL metabolism.^48,51 Diets supplemented with PS have been shown to enhance the abundance of beneficial microbiota species, such as Eubacterium halii, while simultaneously reducing the prevalence of the Erysipelotrichaceae family within the Firmicutes phylum. This bacterial family is suggested to contribute to the development of metabolic disorders.⁵² Plant sterols in the microbiota from a lean population alter the CHOL biotransformation pathway, reducing the generation of CHOL metabolites while enhancing the metabolism of plant sterols. CHOL metabolites coprostanol and coprostanone are considered colon carcinogens.^52,53 The concentration of these metabolites is higher in fermentation in obese vs lean population.⁵³ Moreover, PS contribute to an increase in SCFAs, which may reduce appetite and lower food supply, and help prevent colon cancer.⁵³ However, further investigation is needed to better understand anticancer and hepatoprotective properties of PS.³⁰

Interactions between PS and other CHOL-lowering drugs have also been studied. It has been indicated that the combined action of these compounds reduces CHOL concentration in plasma. A meta-analysis that included 15 randomized clinical trials showed that PS combined with statin treatment, compared with statins alone, decreased the levels of TC and LDL-C by 0.3 mmol/l.⁵⁴ Interestingly, the study showed that statins and ezetimibe also influenced the reduction of PS concentration in plasma, which could be beneficial in patients with phytosterolemia. The study demonstrated that ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations, while statins significantly decreased desmosterol and lathosterol levels.⁵⁵ Ezetimibe and statins administered together lowered all the above-mentioned sterol levels. However, long-term interactions between these substances require further research.^55-57

Filling the gaps in the presented areas can be useful in determining full therapeutic potential of PS and assessing interactions between factors such as genetics, gut microbiota, and drugs, which can be valuable in clinical practice.

Conclusions

PS have gained interest in the management of dyslipidemia and other health conditions due to their cholesterol-lowering, anti-inflammatory, and antioxidant properties. They are being increasingly integrated into lifestyle changes as an adjunct to the statin and ezetimibe treatments aimed at decreasing LDL-C, TC, IDL-B, and Apo-B levels, which is especially beneficial for very-high-risk patients who fail to achieve target LDL-C levels or do not tolerate statins. Genetics and the gut microbiome may affect the efficacy of PS treatment. Due to limited bioavailability of PS within dietary matrices, recent advancements, such as esterification and nanoscale delivery systems, have been studied. However, further research is needed to determine appropriate PS delivery methods, their long-term safety, and interactions with other CHOL-lowering drugs. With individual selection of treatment, PS can become an important factor in the prevention of cardiovascular diseases, metabolic syndrome, and potentially cancer.

Correspondence to

Aleksandra Gąsecka, MD, PhD, First Chair and Department of Cardiology, Medical University of Warsaw, ul. Banacha 1a, 02-097 Warszawa, Poland, phone: +48 22 522 19 51, email: gaseckaa@gmail.com

Received

March 3, 2025.

Revision accepted

April 7, 2025.

Published online

April 17, 2025.

Acknowledgments

None.

Funding

None.

Contribution statement

MŚ and AG conceived the concept of the study. MŚ was in charge of the resources and original draft. MŚ and AG were responsible for the review and editing. MŚ was in charge of the visualization. AG was responsible for the supervision. All authors read and agreed to the submitted version of the manuscript.

AI statement

AI was not used during preparation of the manuscript.

Conflict of interest

None declared.

How to cite

Świerkowska M, Gąsecka A. Therapeutic potential and safety of phytosterols in contemporary clinical practice. Prz Lek Jagiellonian Med Rev. 2025; 77: 17947. doi:10.20452/jmr.2025.17947

1.: Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020; 41: 111-188.
2.: El Omari N, Bakrim S, Khalid A, et al. Unveiling the molecular mechanisms: dietary phytosterols as guardians against cardiovascular diseases. Nat Prod Bioprospect. 2024; 14: 27.Crossref
3.: Zio S, Tarnagda B, Tapsoba F, et al. Health interest of cholesterol and phytosterols and their contribution to one health approach: review. Heliyon. 2024; 10: e40132.Crossref
4.: Simonen P, Nylund L, Vartiainen E, et al. Heart-healthy diets including phytostanol ester consumption to reduce the risk of atherosclerotic cardiovascular diseases. A clinical review. Lipids Health Dis. 2024; 23: 341.Crossref
5.: Makhmudova U, Schulze PC, Lütjohann D, Weingärtner O. Phytosterols and cardiovascular disease. Curr Atheroscler Rep. 2021; 23: 68.Crossref
6.: Cheng Y, Chen Y, Li J, et al. Dietary β-sitosterol regulates serum lipid level and improves immune function, antioxidant status, and intestinal morphology in broilers. Poult Sci. 2020; 99: 1400-1408.Crossref
7.: Gupta R, Sharma AK, Dobhal MP, et al. Antidiabetic and antioxidant potential of β-sitosterol in streptozotocin-induced experimental hyperglycemia. J Diabetes. 2011; 3: 29-37.Crossref
8.: Shen M, Yuan L, Zhang J, et al. Phytosterols: physiological functions and potential application. Foods. 2024; 13: 1754.Crossref
9.: Sun X, Feng X, Zheng D, et al. Ergosterol attenuates cigarette smoke extract-induced COPD by modulating inflammation, oxidative stress and apoptosis in vitro and in vivo. Clin Sci (Lond). 2019; 133: 1523-1536.Crossref
10.: Yongxia Z, Jian X, Suyuan H, et al. Isolation and characterization of ergosterol from Monascus anka for anti-lipid peroxidation properties. J Mycol Med. 2020; 30: 101038.Crossref
11.: Nemat Alla M, Hassan N, Budran I, et al. Stigmasterol alleviates the impacts of drought in flax and improves oil yield via modulating efficient antioxidant and ROS homeostasis. Iran J Plant Physiol. 2022; 1: 3973-3984.
12.: Kirindage K, Jayasinghe AMK, Han EJ, et al. Fucosterol isolated from dietary brown alga Sargassum horneri protects TNF-α/IFN-γ-stimulated human dermal fibroblasts via regulating Nrf2/HO-1 and NF-κB/MAPK pathways. Antioxidants (Basel). 2022; 11: 1429.Crossref
13.: Jie F, Yang X, Yang B, et at. Stigmasterol attenuates inflammatory response of microglia via NF-κB and NLRP3 signaling by AMPK activation. Biomed Pharmacother. 2022; 153: 113317.Crossref
14.: Jayawardena TU, Sanjeewa KKA, Lee HG, et al. Particulate matter-induced inflammation / oxidative stress in macrophages: fucosterol from Padina boryana as a potent protector, activated via NF-κB/MAPK pathways and Nrf2/HO-1 involvement. Mar Drugs. 2020; 18: 628.Crossref
15.: Banach M, Burchardt P, Chlebus K, et al. PTL/KLRWP/PTK/PTDL/PTD/PTNT guidelines on the diagnosis and management of lipid disorders in Poland in 2021 [in Polish]. Nadciśnienie Tętnicze w Praktyce. 2021; 7: 113-122.
16.: Zhang Y-F, Qiao W, Feng H, et al. Effects of phytosterol supplementation on lipid profiles and apolipoproteins: a meta-analysis of randomized controlled trials. Medicine (Baltimore). 2024; 103: e40020.Crossref
17.: Demonty I, Ras RT, van der Knaap HCM, et al. Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake. J Nutr. 2009; 139: 271-284.
18.: Machado VA, Santisteban ARN, Martins CM, et al. Effects of phytosterol supplementation on lipoprotein subfractions and LDL particle quality. Sci Rep. 2024; 14: 11108.Crossref
19.: Palmeiro-Silva YK, Aravena RI, Ossio L, Parro Fluxa J. Effects of daily consumption of an aqueous dispersion of free-phytosterols nanoparticles on individuals with metabolic syndrome: a randomised, double-blind, placebo-controlled clinical trial. Nutrients. 2020; 12: 2392.Crossref
20.: Rideout TC, Marinangeli CPF, Harding SV. Triglyceride-lowering response to plant sterol and stanol consumption. J AOAC Int. 2015; 98: 707-715.Crossref
21.: Ottestad, I, Ose L, Wennersberg MH, et al. Phytosterol capsules and serum cholesterol in hypercholesterolemia: a randomized controlled trial. Atherosclerosis. 2013; 228: 421-425.Crossref
22.: Gylling H, Plat J, Turley S, et al. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis. 2014; 232: 346-360.Crossref
23.: ANSES 2014. ANSES Notice Referral [in French] No. 2010-SA-0057: 1-15.
24.: Pederiva C, Biasucci G, Banderali G, Capra ME. Plant sterols and stanols for pediatric patients with increased cardiovascular risk. Children (Basel). 2024; 11: 129.Crossref
25.: Abdul-Rahman T, Bukhari SMA, Herrera EC, et al. Lipid lowering therapy: an era beyond statins. Curr Probl Cardiol. 2022; 47: 101342.Crossref
26.: Barkas F, Nomikos T, Liberopoulos E, Panagiotakos D. Diet and cardiovascular disease risk among individuals with familial hypercholesterolemia: systematic review and meta-analysis. Nutrients. 2020; 12: 2436.Crossref
27.: Moruisi KG, Oosthuizen W, Opperman AM. Phytosterols / stanols lower cholesterol concentrations in familial hypercholesterolemic subjects: a systematic review with meta-analysis. J Am Coll Nutr. 2006; 25: 41-48.Crossref
28.: Ogbe R. A review of dietary phytosterols: their occurrences, metabolism and health benefits. Asian Journal of Plant Science and Research. 2015; 5: 10-21.
29.: Windler E, Beil F-U, Berthold HK, et al. Phytosterols and cardiovascular risk evaluated against the background of phytosterolemia cases—a German Expert Panel Statement. Nutrients. 2023; 15: 828.Crossref
30.: Miszczuk E, Bajguz A, Kiraga Ł, et al. Phytosterols and the digestive system: a review study from insights into their potential health benefits and safety. Pharmaceuticals. 2024; 17: 557.Crossref
31.: Scholz M, Horn K, Pott J, et al. Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis. Nat Commun. 2022; 13: 143.Crossref
32.: Poli A, Marangoni F, Corsini A, et al. Phytosterols, cholesterol control, and cardiovascular disease. Nutrients. 2021; 13: 2810.Crossref
33.: Jiménez P, Bustamante A, Echeverría F, et al. Metabolic benefits of phytosterols: chemical, nutritional, and functional aspects. Food Rev Int. 2024; 40: 2917-2939.Crossref
34.: Wang T, Ma C, Hu Y, et al. Effects of food formulation on bioavailability of phytosterols: phytosterol structures, delivery carriers, and food matrices. Food Funct. 2023; 14: 5465-5477.Crossref
35.: Yang R, Xue L, Zhang L, et al. Phytosterol contents of edible oils and their contributions to estimated phytosterol intake in the Chinese diet. Foods. 2019; 8: 334.Crossref
36.: Feng S, Wang L, Shao P, et al. A review on chemical and physical modifications of phytosterols and their influence on bioavailability and safety. Crit Rev Food Sci Nutr. 2022; 62: 5638-5657.Crossref
37.: Li X, Xin Y, Mo Y, et al. The bioavailability and biological activities of phytosterols as modulators of cholesterol metabolism. Molecules. 2022; 27: 523.Crossref
38.: Mahdlou Z, Dehkharghani RA, Niazi A, et al. Co-sonicated coacervation for high-efficiency green nanoencapsulation of phytosterols by colloidal non-biotoxic solid lipid nanoparticles. Sci Rep. 2024; 14: 4671.Crossref
39.: Marisa D, Hayatie L, Juliati S, et al. Molecular docking of phytosterol compounds from kelakai (Stenochlaena palustris) as anti-breast cancer. Acta Biochim Indones. 2021; 4: 59.Crossref
40.: Bae H, Song G, Lim W. Stigmasterol causes ovarian cancer cell apoptosis by inducing endoplasmic reticulum and mitochondrial dysfunction. Pharmaceutics. 2020; 12: 488.Crossref
41.: Ramprasath VR, Awad AB. Role of phytosterols in cancer prevention and treatment. J AOAC Int. 2015; 98: 735-738.
42.: Zhao H, Zhang X, Wang M, et al. Stigmasterol simultaneously induces apoptosis and protective autophagy by inhibiting Akt/mTOR pathway in gastric cancer cells. Front Oncol. 2021; 11: 629008.Crossref
43.: Wang S, Zhao W, Sun L, et al. Independent and opposing associations of dietary phytosterols intake and PLCE1 rs2274223 polymorphisms on esophageal squamous cell carcinoma risk. Eur J Nutr. 2021; 60: 4357-4366.Crossref
44.: Gajendran B, Durai P, Madhu Varier K, Chinnasamy A. A novel phytosterol isolated from Datura inoxia, RinoxiaB is a potential cure colon cancer agent by targeting BAX/Bcl2 pathway. Bioorg Med Chem. 2020; 28: 115242.Crossref
45.: Cioccoloni G, Soteriou C, Websdale A, et al. Phytosterols and phytostanols and the hallmarks of cancer in model organisms: a systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2022; 62: 1145-1165.Crossref
46.: Gylling H, Halonen J, Lindholm H, et al. The effects of plant stanol ester consumption on arterial stiffness and endothelial function in adults: a randomised controlled clinical trial. BMC Cardiovasc Disord. 2013; 13: 50.Crossref
47.: Simonen P, Öörni K, Sinisalo J, et al. High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases? Atherosclerosis. 2023; 376: 53-62.Crossref
48.: Deng C, Pan J, Zhu H, Chen ZY. Effect of gut microbiota on blood cholesterol: a review on mechanisms. Foods. 2023; 12: 4308.Crossref
49.: Bridgeman S, Woo HC, Newsholme P, Mamotte C. Butyrate lowers cellular cholesterol through HDAC inhibition and impaired SREBP-2 signalling. Int J Mol Sci. 2022; 23: 15506.Crossref
50.: Li L, Batt SM, Wannemuehler M, et al. Effect of feeding of a cholesterol-reducing bacterium, Eubacterium coprostanoligenes, to germ-free mice. Lab Anim Sci. 1998; 48: 253-255.
51.: Wilson MD, Rudel LL. Review of cholesterol absorption with emphasis on dietary and biliary cholesterol. J Lipid Res. 1994; 35: 943-55.Crossref
52.: Cuevas-Tena M, Gómez del Pulgar E.M, Benítez-Páez A, et al. Plant sterols and human gut microbiota relationship: an in vitro colonic fermentation study. J Funct Food. 2018; 44: 322-329.Crossref
53.: Cuevas-Tena M, Alegria A, Lagarda MJ, Venema K. Impact of plant sterols enrichment dose on gut microbiota from lean and obese subjects using TIM-2 in vitro fermentation model. Journal of Functional Foods. 2019; 54: 164-174.Crossref
54.: Han S, Jiao J, Xu J, et al. Effects of plant stanol or sterol-enriched diets on lipid profiles in patients treated with statins: systematic review and meta-analysis. Sci Rep. 2016; 6: 31337.Crossref
55.: Assmann G, Kannenberg F, Ramey DR, et al. Effects of ezetimibe, simvastatin, atorvastatin, and ezetimibe-statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia. Curr Med Res Opin. 2008; 24: 249-259.
56.: Anagnostis P, Kotsis V, Banach M, Mikhailidis DP. Could lowering phytosterol absorption as part of lipid-lowering therapy have a beneficial effect on residual risk? Metabolites. 2023; 13: 145.Crossref
57.: Lin X, Racette SB, Lefevre M, et al. Combined effects of ezetimibe and phytosterols on cholesterol metabolism: a randomized, controlled feeding study in humans. Circulation. 2011; 124: 596-601.Crossref
58.: Ruiu G, Pinach S, Veglia F, et al. Phytosterol-enriched yogurt increases LDL affinity and reduces CD36 expression in polygenic hypercholesterolemia. Lipids. 2009; 44: 153-160.Crossref
59.: Amir Shaghaghi M, Harding SV, Jones PJH. Water dispersible plant sterol formulation shows improved effect on lipid profile compared to plant sterol esters. Journal of Functional Foods. 2014; 6: 280-289.
60.: Castro Cabezas M, de Vries JH, Van Oostrom AJ, et al. Effects of a stanol-enriched diet on plasma cholesterol and triglycerides in patients treated with statins. J Am Diet Assoc. 2006; 106: 1564-1569.Crossref
61.: Sialvera TE, Pounis GD, Koutelidakis AE, et al. Phytosterols supplementation decreases plasma small and dense LDL levels in metabolic syndrome patients on a westernized type diet. Nutr Metab Cardiovasc Dis. 2012; 22: 843-848.Crossref