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β‐Sitosterol is a major bioactive constituent and the most abundant phytosterol in nuts, seeds, and vegetable oils. It is structurally similar to cholesterol, except for the addition of the ethyl group. The primary benefit of β‐sitosterol is that it lowers the body's absorption of low‐density lipoprotein, or "bad" cholesterol. Research efforts to date and information from the available literature have demonstrated that β‐sitosterol has many pharmacological benefits to improve human health; it effectively prevents heart diseases, cancer, and diabetes. To date, many investigations on β‐sitosterol have been conducted in in vitro and in vivo studies. There are considerable research gaps because there are almost no clinical studies to examine the safety and effectiveness of β‐sitosterol for various human diseases. This review aims to discuss the dietary sources and variations of β‐sitosterol in food crops and how it can successfully prevent cancer and diabetes, including the mechanism underlying these benefits. In addition, we also discuss the research gaps and provide our perspective on future research to propose β‐sitosterol as a nutraceutical candidate to prevent human diseases. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases, including coronary heart disease (CHD), are currently positioned among the leading causes of mortality globally. Risk factors of CHD include, among others, hypercholesterolemia and elevations in systemic inflammation. Functional foods enriched with compounds showing cholesterol-lowering effects are considered one among various dietary and lifestyle intervention strategies to tackle this problem. A CHD-preventive effect of dietary plant sterols has been broadly discussed, not only due to their ability to reduce blood cholesterol level, but also to their proven anti-inflammatory potential. Palm oil is one of the most widely consumed edible oils in the world. Despite its widespread use, especially in Asian countries, no study has been conducted using palm oil as a vehicle for plant sterols. Methods: The aim of the placebo-controlled double-blinded trial presented here was, therefore, to evaluate the effect of palm oil enriched with plant sterols, used as a cooking oil, on lipid profile and systemic inflammation marker in 100 adult hyperlipidemic residents of Bogor, Indonesia. Results: The study has shown a significant reduction in total cholesterol and LDL cholesterol level in study subjects consuming plant sterol-enriched palm oil as a replacement for usual palm oil for cooking, with no similar effect on CRP levels. Conclusions: The study suggests that, along with a healthy diet and lifestyle promotion, incorporating plant sterols in palm oil used for cooking may be an effective strategy to reduce cardiovascular risks in hyperlipidemic individuals. [ABSTRACT FROM AUTHOR]

Objective: We tested the effect of 27-hydroxycholesterol (27OHC) on the expression and synthesis of two membrane transporters involved in sterols extrusion from the intestinal epithelium into the gut lumen: ATP-binding cassette A1 (ABCA1) and G8 (ABCG8). Special attention was given to ABCG8, a key player in the intestinal cell discharge of plant sterols. Methods: Differentiated CaCo-2 intestinal cells were supplemented with 27OHC, and added to the cell incubation medium at a final concentration of 1 or 5 μM. These 27OHC externally added amounts were proven to reach intracellular oxysterol levels within the range of those normally recovered in the human peripheral blood. Results: An up-regulation of the ABCA1 and ABCG8 mRNAs was observed in the CaCo-2 cells supplemented with 27OHC. Moreover, both 1 μM and 5 μM 27OHC induced a net, and steady, statistically significant, increase of both ABCA1 and ABCG8 protein levels. Of interest, the cellular pre-treatment with diphenylene iodonium, a selective inhibitor of NADPH oxidase, i.e. a major intracellular source of reactive oxygen species, fully inhibited the 27OHC enhancement of both ABCA1 and ABCG8 protein synthesis. Conclusion: This in vitro study shows for the first time that the addition of 27OHC to intestinal epithelial cells up-regulates ABCG8, the transporter discharging plant sterols into the gut lumen, besides confirming to induce ABCA1 as well. Importantly, the 27OHC-dependent up-regulation of the two transporters appears to involve a redox mechanism rather than the canonical liver-X-receptors-dependent pathway. Significance statement The 27OHC introduced with the diet might modulate the plant sterol extrusion in the gut, in parallel with that of cholesterol.

Abstract Background Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. Methods This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. Results The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. Conclusion This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.

Diet is crucial for the prevention of colorectal cancer. Whole grains are the source of beneficial compounds for this, such as fiber. The enrichment of wholemeal rye bread with plant sterols (PSs) could increase its beneficial effects. This study aimed to assess the potential antiproliferative effect of this enriched food on colon adenocarcinoma cells (Caco-2) compared with a non-enriched one. After a human oral chewing, simulated semi-dynamic gastrointestinal digestion and colonic fermentation in a simgi® system, fermentation liquids (FLs) obtained were used as treatment for cells. Cytotoxicity assay showed that samples diluted 1/5 (v/v) with DMEM are not toxic for non-tumoral cells, whereas they damage tumoral cells. Samples with PS (FLPS) produced a higher chemopreventive effect (vs. blank) in MTT and apoptosis assays, as well as higher gene expression of TP53 and Casp8. Nevertheless, FL0 (without PS) produced a higher chemopreventive effect in a cell cycle and reduced glutathione and calcium assays, besides producing higher gene expression of Casp3 and lower CCND1. The distinct antiproliferative effect of both FLs is attributed to differences in PSs, short chain fatty acids (lower concentration in FLPS vs. FL0) and antioxidant compounds. These results may support wholemeal rye bread consumption as a way of reducing the risk of colorectal cancer development, although further research would be needed. [ABSTRACT FROM AUTHOR]

The atherosclerotic process begins in childhood and progresses throughout adult age. Hypercholesterolemia, especially familial hypercholesterolemia (FH) and metabolic dysfunctions linked to weight excess and obesity, are the main atherosclerosis risk factors in pediatric patients and can be detected and treated starting from childhood. Nutritional intervention and a healthy-heart lifestyle are cornerstones and first-line treatments, with which, if necessary, drug therapy should be associated. For several years, functional foods enriched with plant sterols and stanols have been studied in the treatment of hypercholesterolemia, mainly as nutritional complements that can reduce LDL cholesterol; however, there is a lack of randomized controlled trials defining their long-term efficacy and safety, especially in pediatric age. This review aims to evaluate what the main published studies on sterols and stanols in pediatric subjects with dyslipidemia have taught us, providing an updated picture of the possible use of these dietary supplements in children and adolescents with dyslipidemia and increased cardiovascular risk. Nowadays, we can state that plant sterols and stanols should be considered as a valuable therapy in pediatric patients with hypercholesterolemia, bearing in mind that nutritional and lifestyle counseling and, when necessary, pharmacologic therapy, are the cornerstones of the treatment in developmental age. [ABSTRACT FROM AUTHOR]

To better explore the effects of adding phytosterol (PS) microcapsules to feed on pig growth performance, nutrient apparent digestibility, and serum biochemical indicators, 200 healthy ternary hybrid Duroc × Landrace × Yorkshire piglets with an average initial weight of 7.53 ± 0.57 kg) were used as experimental subjects, and randomly divided into five groups with four replicates in each group. The control group of pigs was fed the basic diet, while the experimental group received diets supplemented with different PS levels. They were divided into experimental groups 1 to 4 (100 mg/kg to 5 502 mg/kg) according to different dosage added components. The duration of the experiment was 54 days. The results showed that the total triglyceride (TG) index and diarrhoea status in the experimental group were significantly improved compared to the control group (P < 0.05). The increase in PS addition levels was more significant in the change of pig average daily gain (ADG) (P < 0.05), and the difference in average daily weight gain and feed conversion ratio between PS-400 and PS-550 was significant (P 0.05). From the above, plant sterol microcapsules can effectively improve pig growth performance and nutrient apparent digestibility, and improve their blood lipid status.

Plant sterols are well-known natural lipid-lowering agents. The DESCO (Diet and plant sterols in the control of cholesterolemia) study was a single-center, randomized, double-blind, placebo-controlled, two-way crossover clinical trial designed to investigate the effect of a once-a-day ready-to-drink dietary supplement containing 2.5 g of phytosterols on the lipid profile, also in relation to the quality of the diet, in a cohort of 50 Italian individuals with polygenic hypercholesterolemia and low global cardiovascular risk. Eligible individuals were enrolled in a run-in period of 2 weeks. Then, participants who qualified for continuation in the study were randomly allocated (1:1) to a 3-week treatment with either phytosterols or placebo. After a 2-week washout period, enrolled individuals were crossed over to receive the alternative treatment. Dietary supplementation with phytosterols was associated with significant improvement in plasma levels of total cholesterol (TC; −11.8 ± 4.0 mg/dL, p = 0.016), low-density lipoprotein cholesterol (LDL-C; −7.8 ± 7.7 mg/dL, p = 0.021), and apolipoprotein B-100 (Apo B-100, −3.7 ± 4.1 mg/dL, p = 0.048) compared to baseline. The changes in TC and LDL-C were also significant compared to placebo, and greater adherence to the Mediterranean diet was significantly associated with greater reductions in LDL-C. Dietary supplementation with phytosterols was well tolerated and adherence to treatment was high. According to the findings of DESCO, the once-a-day ready-to-drink dietary supplement we tested is able to quickly and significantly decrease plasma levels of TC, LDL-C, and Apo B-100, with a greater effect in individuals more adhering to the Mediterranean dietary pattern. [ABSTRACT FROM AUTHOR]

Studies on the impact of colonic fermentation of plant sterol (PS)-enriched foods using dynamic in vitro models are limited. This study aimed to evaluate the effect of a 72-h dynamic in vitro digestion-colonic fermentation (using the simgi® system) of PS-enriched rye bread on colonic microbial population and short-chain fatty acid (SCFA) and ammonium production. In all colon compartments (ascending colon (AC), transverse colon (TC), and descending colon (DC)) (72 vs. 0 h), a reduction in ammonium concentration (5.7- to 9.4-fold) and an increase in Staphylococcus spp. (1.4- to 2.1-fold), Lactobacillus spp. (1.5-fold), Bifidobacterium spp. (1.3- to 1.5-fold), and Enterococcus spp. (1.4- to 1.6-fold) were observed. In AC and TC, total SCFA decreased (4- and 1.3-fold, respectively), whereas it increased 1.4-fold in DC due to an increase in butyrate content from 4 to 45 mM. These results suggest that PS-enriched rye bread favors the growth of beneficial microbial species and the production of butyrate, a fuel source for enterocytes, thus promoting health benefits. [ABSTRACT FROM AUTHOR]

The main objective was to assess if foods fortified with phytosterols (PS), including plant sterols and plant stanols, reduce low-density lipoprotein cholesterol (LDL-C) concentrations. The secondary objective was to determine the impact of different factors related to PS administration. The search was carried out in MEDLINE, EMBASE, Web of Science, Scopus and The Cochrane Central Register of Controlled Trials (CENTRAL) databases up to March 2023. The meta-analysis was registered in the PROSPERO database (CRD42021236952). From a total of 223 studies, 125 were included. On average, PS lowered LDL-C 0.55 mmol/L [95% confidence interval (CI) = 10.82–12.67], and this decrease was significantly maintained for all analysed subgroups. A greater reduction in LDL-C levels was detected in relation to a higher daily PS dosage. The food format "Bread, biscuits, cereals", conditioned a lower decrease of 0.14 mmol/L (95%CI -8.71 to −2.16) in LDL-C levels, compared to the predominant food format group of "butter, margarine, spreads". No significant differences were detected with the other subgroups (treatment duration, intake pattern, number of daily intakes and concomitant statin treatment). The present meta-analysis supported that the use of PS-fortified foods had a beneficial effect on LDL-C lowering. In addition, it was observed that the factors that influence a decline LDL-C levels were PS dose as well as the food format in which they were consumed. • Use of PS-fortified foods had a beneficial effect on LDL-C reduction, about a 0.55 mmol/L. • The factors that influence LDL-C decreasing levels were the dose of PS and the food format in which they were consumed. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable causes. Lifestyle intervention constitutes the first step in cholesterol management and includes dietary modifications along with the use of functional foods and supplements. Functional foods enriched with plant sterols/stanols have become the most widely used nonprescription cholesterol-lowering approach, despite the lack of randomized trials investigating their long-term safety and cardiovascular efficacy. The cholesterol-lowering effect of plant-sterol supplementation is well-established and a potential beneficial impact on other lipoproteins and glucose homeostasis has been described. Nevertheless, experimental and human observational studies investigating the association of phytosterol supplementation or circulating plant sterols with various markers of atherosclerosis and ASCVD events have demonstrated controversial results. Compelling evidence from recent genetic studies have also linked elevated plasma concentrations of circulating plant sterols with ASCVD presence, thus raising concerns about the safety of phytosterol supplementation. Thus, the aim of this review is to provide up-to-date data on the effect of plant sterols/stanols on lipid-modification and cardiovascular outcomes, as well as to discuss any safety issues and practical concerns. [ABSTRACT FROM AUTHOR]

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ABSTRACT Plant sterol intake is widely recommended for patients with cardiovascular risk factors based on the inhibitory effect on intestinal cholesterol absorption. Although plant sterols, once absorbed, can promote atherosclerosis, their intake is believed to be safe because of poor absorption, except in rare hyperabsorbers with homozygous ABCG5/8 mutations. We report a case of new‐onset type 1 diabetes accompanied by hypercholesterolemia. At the initial presentation with diabetic ketoacidosis, the patient showed marked hypercholesterolemia. Whole‐exome sequencing revealed a heterozygous pathogenic variant in ABCG5 (p.R419H). The initial serum plant sterol levels were markedly high (sitosterol 32.5 μg/mL, campesterol 66.0 μg/mL), close to the range observed in patients with homozygous ABCG5/8 mutations, which were largely reduced by insulin treatment without ezetimibe. The addition of ezetimibe normalized plant sterol levels. These findings provide the first evidence that uncontrolled diabetes plays a causal role in the pathogenesis of phytosterolemia.

Abstract Background: Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL. Objectives: To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas. Methods: We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL. Results: Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas. Conclusion The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL.

Purpose of Review: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. Recent Findings: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Summary: Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative. [ABSTRACT FROM AUTHOR]

Background: Non-cholesterol sterols, as well as plant sterols, cross the blood–brain barrier and, thus, can be incorporated into cell membranes, affecting the cell's inflammatory response. The aim of our work was to develop an analytical protocol for a quantitative assessment of the sterol composition within the membrane microdomains of microglia. Methods: A protocol for cell membrane isolation using OptiPrepTM gradient ultracentrifugation, in combination with a targeted mass spectrometry (LC-MS/MS)-based assay, was developed and validated for the quantitative analysis of free sterols in microglia cell membranes. Results: Utilizing an established LC-MS/MS assay, cholesterol and seven non-cholesterol sterols were analyzed with a limit of detection from 0.001 to 0.05 mg/L. Applying the detergent-free isolation of SIM-A9 microglia cell membranes, cholesterol (CH), desmosterol (DE), lanosterol (LA) stigmasterol (ST), beta-sitosterol (SI) and campesterol (CA) were quantified with coefficients of variations between 6 and 29% (fractions 4–6, n = 5). The highest concentrations of non-CH sterols within the microglia plasma membranes were found in the microdomain region (DE>LA>SI>ST>CA), with ratios to CH ranging from 2.3 to 435 lower abundancies. Conclusion: By applying our newly developed and validated analytical protocol, we show that the non-CH sterol concentration is about 38% of the total sterol content in microglia membrane microdomains. Further investigations must clarify how changes in the non-sterol composition influence membrane fluidity and cell signaling. [ABSTRACT FROM AUTHOR]

The atherosclerotic process begins in childhood and progresses throughout adult age. Hypercholesterolemia, especially familial hypercholesterolemia (FH) and metabolic dysfunctions linked to weight excess and obesity, are the main atherosclerosis risk factors in pediatric patients and can be detected and treated starting from childhood. Nutritional intervention and a healthy-heart lifestyle are cornerstones and first-line treatments, with which, if necessary, drug therapy should be associated. For several years, functional foods enriched with plant sterols and stanols have been studied in the treatment of hypercholesterolemia, mainly as nutritional complements that can reduce LDL cholesterol; however, there is a lack of randomized controlled trials defining their long-term efficacy and safety, especially in pediatric age. This review aims to evaluate what the main published studies on sterols and stanols in pediatric subjects with dyslipidemia have taught us, providing an updated picture of the possible use of these dietary supplements in children and adolescents with dyslipidemia and increased cardiovascular risk. Nowadays, we can state that plant sterols and stanols should be considered as a valuable therapy in pediatric patients with hypercholesterolemia, bearing in mind that nutritional and lifestyle counseling and, when necessary, pharmacologic therapy, are the cornerstones of the treatment in developmental age.

BackgroundNon-cholesterol sterols are validated markers for fractional intestinal cholesterol absorption (cholestanol) and endogenous cholesterol synthesis (lathosterol). This study's objective was to evaluate markers for cholesterol synthesis and absorption in children exposed to two different intravenous lipid emulsions that rapidly change serum plant sterol concentrations as part of their parenteral nutrition (PN).MethodsSerum samples from two different studies were used: (1) nine PN-dependent children with intestinal failure associated liver disease (IFALD) whose soy-based, plant sterol-rich lipid (SO) was replaced with a fish-based, plant sterol-poor (FO) lipid; and (2) five neonates prescribed SO after birth. In the first study, samples were collected at baseline (prior to FO initiation) and after 3 and 6 months of FO. In study 2, samples were collected at 1 and 3 weeks of age.ResultsIn study 1, a 7-fold reduction in campesterol, a 12-fold reduction in sitosterol, and a 15-fold reduction in stigmasterol was observed 6 months after switching to FO. Serum cholesterol concentrations did not change, but cholesterol-standardized lathosterol increased (3-fold) and cholesterol-standardized cholestanol decreased (2-fold). In study 2, after 3 weeks of SO, sitosterol and campesterol concentrations increased 4-5 fold. At the same time, cholesterol-standardized lathosterol increased 69% and cholesterol-standardized cholestanol decreased by 29%.ConclusionBased on these finding we conclude that changes in serum plant sterol concentrations might have direct effects on endogenous cholesterol synthesis, although this needs to be confirmed in future studies. Moreover, we speculate that this changed synthesis subsequently affects intestinal cholesterol absorption.

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20–40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies. [ABSTRACT FROM AUTHOR]

Background: No pharmacological treatment is yet approved for non-alcoholic fatty liver disease (NAFLD). Plant sterols have shown healthy properties beyond lowering LDL-cholesterol, including lowering triglycerides and lipoprotein plasma levels. Despite pre-clinical data suggesting their involvement in liver fat control, no clinical study has yet been successful. Aims: Testing a sub-micron, free, phytosterol dispersion efficacy on NAFLD. Methods: A prospective, uncontrolled pilot study was carried out on 26 patients with ≥17.4% liver steatosis quantified by magnetic resonance imaging. Subjects consumed daily a sub-micron dispersion providing 2 g of phytosterols. Liver fat, plasma lipids, lipoproteins, liver enzymes, glycemia, insulinemia, phytosterols, liposoluble vitamins and C-reactive protein were assessed at baseline and after one year of treatment. Results: Liver steatosis relative change was −19%, and 27% of patients reduced liver fat by more than 30%. Statistically and clinically significant improvements in plasma triglycerides, HDL-C, VLDL and HDL particle number and C-reactive protein were obtained, despite the rise of aspartate aminotransferase, glycemia and insulinemia. Though phytosterol plasma levels were raised by >30%, no adverse effects were presented, and even vitamin D increased by 23%. Conclusions: Our results are the first evidence in humans of the efficacy of submicron dispersible phytosterols for the treatment of liver steatosis, dyslipidemia and inflammatory status in NAFLD. [ABSTRACT FROM AUTHOR]

Cell death program of red blood cells (RBCs), called eryptosis, is characterized by activation of caspases and scrambling of membrane phospholipids with externalization of phosphatidylserine (PS). Excessive eryptosis confers a procoagulant phenotype and is implicated in impairment of microcirculation and increased prothrombotic risk. It has recently been reported that cigarette smokers have high levels of circulating eryptotic erythrocytes, and a possible contribution of eryptosis to the vaso-occlusive complications associated to cigarette smoke has been postulated. In this study, we demonstrate how a mixture of plant sterols (MPtS) consisting of β-sitosterol, campesterol and stigmasterol, at serum concentration reached after ingestion of a drink enriched with plant sterols, inhibits eryptosis induced by cigarette smoke extract (CSE). Isolated RBCs were exposed for 4 h to CSE (10–20% v/v). When RBCs were co-treated with CSE in the presence of 22 µM MPtS, a significant reduction of the measured hallmarks of apoptotic death like assembly of the death-inducing signaling complex (DISC), PS outsourced, ceramide production, cleaved forms of caspase 8/caspase 3, and phosphorylated p38 MAPK, was evident. The new beneficial properties of plant sterols on CSE-induced eryptosis presented in this work open new perspectives to prevent the negative physio-pathological events caused by the eryptotic red blood cells circulating in smokers. [ABSTRACT FROM AUTHOR]

Diet is crucial for the prevention of colorectal cancer. Whole grains are the source of beneficial compounds for this, such as fiber. The enrichment of wholemeal rye bread with plant sterols (PSs) could increase its beneficial effects. This study aimed to assess the potential antiproliferative effect of this enriched food on colon adenocarcinoma cells (Caco-2) compared with a non-enriched one. After a human oral chewing, simulated semi-dynamic gastrointestinal digestion and colonic fermentation in a simgi® system, fermentation liquids (FLs) obtained were used as treatment for cells. Cytotoxicity assay showed that samples diluted 1/5 (v/v) with DMEM are not toxic for non-tumoral cells, whereas they damage tumoral cells. Samples with PS (FLPS) produced a higher chemopreventive effect (vs. blank) in MTT and apoptosis assays, as well as higher gene expression of TP53 and Casp8. Nevertheless, FL0 (without PS) produced a higher chemopreventive effect in a cell cycle and reduced glutathione and calcium assays, besides producing higher gene expression of Casp3 and lower CCND1. The distinct antiproliferative effect of both FLs is attributed to differences in PSs, short chain fatty acids (lower concentration in FLPS vs. FL0) and antioxidant compounds. These results may support wholemeal rye bread consumption as a way of reducing the risk of colorectal cancer development, although further research would be needed.

Studies on the impact of colonic fermentation of plant sterol (PS)-enriched foods using dynamic in vitro models are limited. This study aimed to evaluate the effect of a 72-h dynamic in vitro digestion-colonic fermentation (using the simgi® system) of PS-enriched rye bread on colonic microbial population and short-chain fatty acid (SCFA) and ammonium production. In all colon compartments (ascending colon (AC), transverse colon (TC), and descending colon (DC)) (72 vs. 0 h), a reduction in ammonium concentration (5.7- to 9.4-fold) and an increase in Staphylococcus spp. (1.4- to 2.1-fold), Lactobacillus spp. (1.5-fold), Bifidobacterium spp. (1.3- to 1.5-fold), and Enterococcus spp. (1.4- to 1.6-fold) were observed. In AC and TC, total SCFA decreased (4- and 1.3-fold, respectively), whereas it increased 1.4-fold in DC due to an increase in butyrate content from 4 to 45 mM. These results suggest that PS-enriched rye bread favors the growth of beneficial microbial species and the production of butyrate, a fuel source for enterocytes, thus promoting health benefits.

Introduction: Non-communicable diseases are a cluster of metabolic diseases, which include type-2 diabetes, cancer, and cardiovascular diseases (CVDs). The aim of the current research was to incorporate dietary fibers (mucilage) and phytosterol for enriching chia seeds oil for producing new dietary supplements for cardio-protection from oxidative stress, inflammation, and dyslipidemia. Methods: Fatty acids profile, phytosterols, and phenolic compounds content of the prepared dietary supplement were assessed. The cardioprotective potency of the dietary supplement was evaluated in rats fed on a high-fat diet for a month. Biochemical parameters related to inflammation, oxidative stress, lipid profile, cardiac enzymes, and kidney function were determined in all rats. Results: The results revealed that dietary supplement was rich in omega-3 fatty acids. Beta-sitosterol and campesterol were the major phytosterols in chia seeds oil dietary supplement. Phenolic compounds were present by 25.9 ± 1.202 mg gallic acid equivalent (GAE)/g dietary supplements. Rats fed on the high-fat diet showed significant elevation (P < 0.05) in inflammatory markers, oxidative stress, dyslipidemia, and cardiac enzymes in association with the elevation of kidney function compared with normal rats. Administration of both doses of dietary supplement significantly (P < 0.05) improved all the studied biochemical parameters. The high dose of the dietary supplement was promising in the reduction of inflammatory markers, oxidative stress, and improved dyslipidemia in accordance with the reduction of all cardiac enzymes and kidney function. Conclusion: Dietary supplements investigated in the current research showed cardioprotective potency through its anti-inflammatory and dyslipidemic activities, which may be attributed to the presence of phenolic compounds, omega-3 fatty acids, phytosterols, and soluble dietary fibers.

Current evidence indicates that foods with added plant sterols or stanols can lower serum levels of low-density lipoprotein cholesterol. This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Participants discussed issues including, but not limited to, the health benefits of plant sterols and stanols beyond cholesterol lowering, the role of plant sterols and stanols as adjuncts to diet and drugs, and the challenges involved in measuring plant sterols and stanols in biological samples. Variations in interindividual responses to plant sterols and stanols, as well as the personalization of lipid-lowering therapies, were addressed. Finally, the clinical aspects and treatment of sitosterolemia were reviewed. Although plant sterols and stanols continue to offer an efficacious and convenient dietary approach to cholesterol management, long-term clinical trials investigating the endpoints of cardiovascular disease are still lacking.

Plant sterol intake is widely recommended for patients with cardiovascular risk factors based on the inhibitory effect on intestinal cholesterol absorption. Although plant sterols, once absorbed, can promote atherosclerosis, their intake is believed to be safe because of poor absorption, except in rare hyperabsorbers with homozygous ABCG5/8 mutations. We report a case of new‐onset type 1 diabetes accompanied by hypercholesterolemia. At the initial presentation with diabetic ketoacidosis, the patient showed marked hypercholesterolemia. Whole‐exome sequencing revealed a heterozygous pathogenic variant in ABCG5 (p.R419H). The initial serum plant sterol levels were markedly high (sitosterol 32.5 μg/mL, campesterol 66.0 μg/mL), close to the range observed in patients with homozygous ABCG5/8 mutations, which were largely reduced by insulin treatment without ezetimibe. The addition of ezetimibe normalized plant sterol levels. These findings provide the first evidence that uncontrolled diabetes plays a causal role in the pathogenesis of phytosterolemia. [ABSTRACT FROM AUTHOR]

Background: Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL. Objectives: To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas. Methods: We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL. Results: Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas. Conclusion: The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL. [ABSTRACT FROM AUTHOR]

Plant sterols (PSs) exhibit intrinsic functions such as antibacterial effects. Their effects simultaneously on both host-mediated and bacteria-mediated pathogenesis are not yet fully understood. We hypothesized that when absorptive cells, defensive cells and detoxer cells are cultured together, their convergent response to an infectious pathogen depends on the molecular mimicry between the ingested sterols and their own defensive lipids. A human triple cell co-culture model incorporating colonocytes, macrophages, and hepatocytes was established. Cocultures were stimulated with Klebsiella pneumoniae 52145 (Kp52145) in the presence of pure plant sterol (β-sitosterol, PS) for six hours. Changes in the structural health markers of the stimulated cocultured cells and their immune response and biochemical markers of pathogenicity were determined. PS significantly inhibited the secretion of cytokines induced by Kp52145. Cell viability was higher in the Kp52145+PS group compared to the Kp52145 alone group. PS decreased Kp52145-induced marker of pathogenicity (SOD), accompanied by reduced levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), mannose binding lectin (MBL), and pentraxin 3 (PTX3) which are the mediators and enzymes associated with the inflammatory response to an infectious-inflamed milieu. PS recovered Kp52145-decreased peroxidase (POX), catalase (CAT), complement component 3 (C3), and high-density lipoprotein cholesterol (HDL-C) values. Convergence of ingested plant sterols and host eukaryotic cell-derived defensive lipids mitigates the disruptive effects of bacterial toxic effector molecules. Structural or immunological similarities (molecular mimicry) between ingested plant sterols and host defensive lipids play an important role in modulating bacterial signalling that occurs at the pathogen-host interface and in the mitigation of infection- and inflammation-driven pathological processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Plant sterols (PS) have been shown to lower blood lipid-lipoproteins concentrations and may serve as a potential functional ingredient for cardiovascular disease (CVD) risk management. However, there are limited studies examining this effect in individuals with metabolic syndrome (MetS). The aim of this study was to evaluate the effects of PS-enriched food consumption as part of a healthy dietary pattern (HDP) on blood pressure and endothelial function in Singaporean adults with MetS., Methods and Results: This was a 12-week, crossover, randomized controlled trial with a 4-week washout period. Thirteen subjects were instructed to consume an HDP diet either with normal soy milk (control group) or with PS (2 g/day)-enriched soy milk (PS group) for 4 weeks. Blood lipid-lipoproteins and glucose concentrations, blood pressure, and endothelial function-related indicators (flow-mediated dilation, total plasma nitrate/nitrite and endothelin-1, circulating endothelial progenitor cells) were assessed before and after the intervention. Systolic blood pressure [mean change, PS group: -4.0 ± 3.7 mmHg; control group: 5.9 ± 2.5 mmHg (P Interaction  = 0.01)] and long-term CVD risk [mean change, PS group: -0.2 ± 1.0 %; control group: 2.7 ± 1.3 % (P Interaction  = 0.03)] decreased following PS consumption. No changes were observed in the other endothelial function-related outcomes., Conclusions: Consumption of PS-enriched food with an HDP diet may lower blood pressure and long-term CVD risk in adults with MetS., Clinical Trial Registration: NCT03723330, https://clinicaltrials.gov/., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The current study was designed to explore the effect of fermented camel milk, plant sterols and their combination on the blood levels of sd-LDL and atherogenicity in rats fed on high-fat-cholesterol diets (HFC). Forty male Wistar rats were distributed into five groups: Normal control (NC), Positive control (PC, HFC), plant sterol (PS, HFC containing 1% (w/w) β-sitosterol:Stigmasterols; 9:1), FM (HFC containing 4% (w/w) lyophilized fermented camel milk), and PSFM (HFC containing 1% (w/w) plant sterols +4% (w/w) lyophilized fermented camel milk). Antioxidant activity showed that β-sitosterol had the highest radical scavenging activity, followed by fermented camel milk and stigmasterol (p < 0.05). Feeding rats on HFC for 8 weeks resulted in a significant (p < 0.05) increase in blood lipids of PC group compared with NC group. Administration of PS, FM, and PSFM resulted in a significant reduction in atherogenic index (50, 24.5, and 41.5 %, p < 0.05), and sd-LDL levels (73, 45, and 59%, p < 0.05), respectively. Only the FM group showed a significant reduction in triglycerides levels of rats. Administration of PS, FM and PSFM decreased serum MDA levels significantly by 58.7, 45.4, and 69% (p < 0.05), and increased total antioxidant capacity by 35.9, 84.8, and 38.3% (p < 0.05), respectively. This is the first report to the best of our knowledge that shows fermented camel milk enriched with plant sterol could reduce atherogenesis and cardiovascular diseases activity via inhibition of the status of small dense LDL and oxidative stress.

Abstract Background Increased physical activity is inversely related to the risk to develop cardiovascular disease (CVD). In a recent systematic review, it was reported that CVD patients had an increased cholesterol absorption and a decreased synthesis as compared with control participants. As increased physical activity levels reduce CVD risk, we hypothesized that exercise training will reduce cholesterol absorption and increase endogenous cholesterol synthesis in older overweight and obese men. Methods A randomized, controlled, crossover trial was performed. Seventeen apparently healthy older overweight and obese men were randomized to start with an aerobic exercise or no-exercise control period for 8 weeks, separated by 12 weeks washout. Fasting serum total cholesterol (TC) and non-cholesterol sterol concentrations were measured at baseline, and after 4 and 8 weeks. Results The aerobic exercise program did not affect serum TC concentrations. In addition, exercise did not affect TC-standardized serum concentrations of sitosterol and cholestanol that are markers for cholesterol absorption. However, a trend for reduced TC-standardized campesterol concentrations, which is another validated marker for cholesterol absorption, was observed as compared with control. Lathosterol concentrations, reflecting cholesterol synthesis, did not differ between both periods. Conclusions Aerobic exercise training for 8 weeks did not lower serum TC concentrations in older overweight and obese men, but a trend towards a decrease in the cholesterol absorption marker campesterol was found. The cholesterol synthesis marker lathosterol did not change. Trial registration posted on www.clinicaltrials.gov as NCT03272061 on 7 September 2017.

Dietary cholesterol (C) is a major contributor to the endogenous C pool, and it affects the serum concentration of total C, particularly the low-density lipoprotein cholesterol (LDL-C). A high serum concentration of LDL-C is associated with an increased risk for atherosclerosis and cardiovascular diseases. This concentration is dependent on hepatic C metabolism creating a balance between C input (absorption and synthesis) and C elimination (conversion to bile acids and fecal excretion). The daily C absorption rate is determined by dietary C intake, biliary C secretion, direct trans-intestinal C excretion (TICE), and the fractional C absorption rate. Hepatic C metabolism coordinates C fluxes entering the liver via chylomicron remnants (CMR), LDL, high-density lipoproteins (HDL), hepatic C synthesis, and those leaving the liver via very low-density lipoproteins (VLDL), biliary secretion, and bile acid synthesis. The knowns and the unknowns of this C homeostasis are discussed. [ABSTRACT FROM AUTHOR]

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study. [ABSTRACT FROM AUTHOR]

New sources of bioactive compounds are constantly explored for reformulating healthier foods. This work aimed to explore and characterize the fatty acid profile and sterol content of three non‐conventional oils used in functional food products (hempseed oil, moringa oil, and echium oil) and to compare them with two conventional ones (extra virgin olive oil [EVOO] and linseed oil). Oxidative stability was assessed by determining their acidity value and peroxide content. All oils showed adequate values for acidity and oxidation status. Echium and hempseed oils showed a high content of polyunsaturated fatty acids (>70%), especially omega‐3 fatty acids, while moringa oil was rich in oleic acid. Echium oil, hempseed oil, and moringa oil presented higher sterol content than EVOO, but lower than that of linseed oil. Sitosterol was the most abundant sterol in all samples (97.88–275.36 mg/100 g oil), except in echium oil, where campesterol (170.62 mg/100 g oil) was the major sterol. Squalene was only found in significant amounts in EVOO. In conclusion, non‐conventional oils seem to be interesting sources of bioactive compounds and have great potential for the food industry. Practical Application: Non‐conventional vegetable oils can be used as alternative sources of lipids in a variety of food products. Additionally, these oils have great potential to be included in the formulation of functional ingredients for the delivery of omega‐3 fatty acids, antioxidants, fiber, among others. [ABSTRACT FROM AUTHOR]

Plant sterols/phytosterols (PSs) are molecules with a similar structure to cholesterol that have a recognized effect on elevated LDL concentrations (LDL-c). PSs are used as a natural therapy against elevated LDL-c in combination with a healthy diet and exercise. A systematic review was performed to evaluate the efficacy of PS-enriched foods in the treatment of hypercholesterolemia. Randomized controlled clinical studies reporting the use of PS-enriched foods to reduce LDL-c among adult individuals were retrieved and assessed for risk of bias. Meta-analyses were performed to assess changes in LDL-c by treatment, food matrix, LDL-c range, sterols dosage and risk of bias (RoB). In the 13 studies analyzed, LDL-c in PS-treated participants decreased by an average of 12.14 (8.98; 15.29) mg/dL. PS administration was statistically more effective in patients with LDL-c ≥ 140 mg/dL and for PS dosages > 2 g/day. It can be concluded that PSs can be used as an important primary prevention measure for hypercholesterolemia and as tertiary prevention for cardiovascular events in patients who already have mild to moderate LDL-c. However, in severe hypercholesterolemia and in cases of familial hypercholesterolemia, it is necessary to combine dietary treatment with the use of statins. [ABSTRACT FROM AUTHOR]

Background The consumption of 2 g/d plant sterols (PSs) reduces circulating LDL cholesterol by ≤10%. The degree of LDL cholesterol lowering was associated with specific apolipoprotein E [ APOE , Reference SNP (rs)429358] and cholesterol 7α-hydroxylase (CYP7A1 , rs3808607) genosets in previous post hoc analyses of randomized controlled trials. However, because post hoc analyses do not conform to the randomization model, there is a greater potential that the findings could be due to type I error, thus warranting validation through an a priori–designed intervention trial. Objectives The GenePredict Plant Sterol study (GPS) was designed to validate associations of LDL cholesterol lowering with specific APOE and CYP7A1 genosets through a priori recruitment of individuals carrying prespecified genosets. Methods A 2-center, double-blind, placebo-controlled, randomized 2-period crossover dietary intervention with 2 g/d PS for 28 d with a minimum 28-d washout was undertaken from July 2017 to December 2019. A priori recruitment of individuals with slightly elevated LDL cholesterol was based on genosets of APOE isoforms and CYP7A1 rs3808607. Randomization was performed with stratification by sex and genoset. Results The recruitment target of 64 participants with prespecified genosets could not be reached, despite the screening of 477 individuals; 42 participants completed the intervention trial. Reductions in LDL cholesterol were similar across all 3 genosets (–0.298 ± 0.164, –0.357 ± 0.115, –0.293 ± 0.109 mmol/L; P  = 0.0002 overall; P  = 0.9126 for treatment × genoset), providing evidence that the shortfall in recruitment might not have stopped the trial from meeting the objective. Conclusions APOE and CYP7A1 genotypes did not influence the efficacy of LDL cholesterol reductions upon dietary intervention with PSs. Findings of previous post hoc analyses could not be validated in a trial using a priori genotype-based recruitment. Obtaining adequate numbers of participants is challenging in trials using genoset-based recruitment, even for common variants. [ABSTRACT FROM AUTHOR]

Background: Many hyperlipidemic patients prescribed β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors (statins) are unable or unwilling to take them. A hedonically acceptable snack-based solution formulated from cholesterol-lowering food ingredients could represent a therapeutic alternative but has not been tested in this population.Objectives: To evaluate the effect of snacks containing a compendium of functional bioactives on fasting LDL cholesterol in statin candidates unwilling to use or intolerant to ≥1 statin drug. Secondary outcomes included changes in circulating total cholesterol (TC), triglycerides, HDL cholesterol, fasting glucose, insulin, and high-sensitivity C-reactive protein concentrations, as well as effects of single-nucleotide polymorphisms (SNPs) on outcome.Methods: This multicenter, randomized, double-blind, free-living crossover study was composed of 2 regimented phases of 4 wk each, separated by a 4-wk washout. Eighteen men and 36 women, with a mean ± SD age of 49 ± 12 y and mean ± SD LDL cholesterol of 131 ± 32.1 mg/dL,  were instructed to ingest a variety of ready-to-eat snacks twice daily as a substitute for something they were consuming already. Other behavior changes were actively discouraged. Treatment products provided ≥5 g fiber, 1000 mg ω-3 (n-3) fatty acids, 1000 mg phytosterols, and 1800 μmol antioxidants per serving. Control products were calorie-matched like-items drawn from the general grocery marketplace. Serum lipids were measured at baseline and the end of each phase and compared using the ANOVA model. Compliance to study foods was confirmed by serum 18:3n-3 concentration assessment.Results: Comparing intervention phase endpoints, LDL cholesterol was reduced a mean ± SD of 8.80 ± 1.69% (P < 0.0001), and TC was reduced a mean ± SD of 5.08 ± 1.12% (P < 0.0001) by treatment foods compared with control foods, whereas effects on other analytes did not differ between treatments. SNPs were not significantly related to outcomes (P ≥ 0.230). Compliance with study foods was 95%.Conclusions: Consumption of hedonically acceptable snacks containing a compendium of cholesterol-lowering bioactive compounds can rapidly and meaningfully reduce LDL cholesterol in adult patients unable or unwilling to take statin drugs. This trial was registered at clinicaltrials.gov as NCT02341924. [ABSTRACT FROM AUTHOR]

Abstract Background Functional food ingredients and natural health products have been demonstrated to reduce disease risk and thereby help to lower health care costs across populations at risk for chronic or degenerative diseases. However, typically a wide range of interindividual variability exists in response across individuals to nutritional and natural health product bioactives, such as plant sterols (PS). This study aims to determine and utilize information on the associations between genosets and the degree of responsiveness to dietary PS intervention, with a long-term objective of developing genetic tests to predict responses to PS. Methods This clinical trial is designed as a double-blind, placebo controlled, randomized two-period crossover study. Sixty-four eligible participants with the specific a priori-determined single nucleotide polymorphisms (SNPs) associated with a responsiveness to PS will consume PS or a placebo treatment for two 4-week periods. The PS treatment consists of two daily single portions of margarine, each providing 1 g PS during the PS period (2.0 g/day of PS in total). The placebo will be an identical margarine containing no added PS. Low-density lipoprotein cholesterol (LDL-C) responsiveness to the controlled administration of PS will be investigated as the primary outcome, and the associations between interindividual genoset variabilities and response to PS consumption will be determined. Discussion This research will provide further insight into whether the associations between previously identified SNPs and the response of LDL-C to PS consumption can be used in a predictive manner. It will also provide insight into the complexities of undertaking a nutrigenetic trial with prospective recruitment based on genotype. Trial registration ClinicalTrials.gov : Identifier: NCT02765516 . Registered on 6 May 2016.

Background: Non-cholesterol sterols, as well as plant sterols, cross the blood–brain barrier and, thus, can be incorporated into cell membranes, affecting the cell’s inflammatory response. The aim of our work was to develop an analytical protocol for a quantitative assessment of the sterol composition within the membrane microdomains of microglia. Methods: A protocol for cell membrane isolation using OptiPrepTM gradient ultracentrifugation, in combination with a targeted mass spectrometry (LC-MS/MS)-based assay, was developed and validated for the quantitative analysis of free sterols in microglia cell membranes. Results: Utilizing an established LC-MS/MS assay, cholesterol and seven non-cholesterol sterols were analyzed with a limit of detection from 0.001 to 0.05 mg/L. Applying the detergent-free isolation of SIM-A9 microglia cell membranes, cholesterol (CH), desmosterol (DE), lanosterol (LA) stigmasterol (ST), beta-sitosterol (SI) and campesterol (CA) were quantified with coefficients of variations between 6 and 29% (fractions 4–6, n = 5). The highest concentrations of non-CH sterols within the microglia plasma membranes were found in the microdomain region (DE>LA>SI>ST>CA), with ratios to CH ranging from 2.3 to 435 lower abundancies. Conclusion: By applying our newly developed and validated analytical protocol, we show that the non-CH sterol concentration is about 38% of the total sterol content in microglia membrane microdomains. Further investigations must clarify how changes in the non-sterol composition influence membrane fluidity and cell signaling.

This study evaluated the impact of different digestion conditions (adult and senior) on lipolysis and bioaccessibility of plant sterols (PS) and phytosterol oxidation products (POPs) in PS-enriched wholemeal rye bread. Under adult digestion conditions, the addition of gastric lipase (GL) reduced lipolysis products (by 6.1% for free fatty acids and 11.7% for monoacylglycerols) and the bioaccessibility of PS by 6.7%, compared to the control. In digestion with both GL and cholesterol esterase (CE), these reductions were 12.9, 20.1, and 11.3%, respectively. Both modifications (GL and GL + CE) increased the bioaccessibility of POPs by 4.5-4.0%. When simulating the elderly digestion, the modified gastric and intestinal phases did not alter PS bioaccessibility but decreased POPs bioaccessibility by 21.8% compared to control, along with reduced lipolysis. Incorporating GL and CE thus approached physiological conditions and influenced lipid digestion. Elderly simulated digestion conditions resulted in a positive outcome by maintaining PS bioaccessibility while reducing potentially harmful POPs.

Background: Increased physical activity is inversely related to the risk to develop cardiovascular disease (CVD). In a recent systematic review, it was reported that CVD patients had an increased cholesterol absorption and a decreased synthesis as compared with control participants. As increased physical activity levels reduce CVD risk, we hypothesized that exercise training will reduce cholesterol absorption and increase endogenous cholesterol synthesis in older overweight and obese men. Methods: A randomized, controlled, crossover trial was performed. Seventeen apparently healthy older overweight and obese men were randomized to start with an aerobic exercise or no-exercise control period for 8 weeks, separated by 12 weeks washout. Fasting serum total cholesterol (TC) and non-cholesterol sterol concentrations were measured at baseline, and after 4 and 8 weeks. Results: The aerobic exercise program did not affect serum TC concentrations. In addition, exercise did not affect TC-standardized serum concentrations of sitosterol and cholestanol that are markers for cholesterol absorption. However, a trend for reduced TC-standardized campesterol concentrations, which is another validated marker for cholesterol absorption, was observed as compared with control. Lathosterol concentrations, reflecting cholesterol synthesis, did not differ between both periods. Conclusions: Aerobic exercise training for 8 weeks did not lower serum TC concentrations in older overweight and obese men, but a trend towards a decrease in the cholesterol absorption marker campesterol was found. The cholesterol synthesis marker lathosterol did not change. Trial registration: posted on www.clinicaltrials.gov as NCT03272061 on 7 September 2017. [ABSTRACT FROM AUTHOR]

Dietary plant sterols, such as campesterol and sitosterol, reduce plasma cholesterol concentrations, but any relationship to plaque development and CVD remains unclear. Some epidemiologic studies have suggested that elevated plasma plant sterol concentrations are atherogenic, including the Framingham Offspring Study that identified a positive association between plant sterol concentrations and CVD status. We hypothesized that this suggested atherogenicity relates to the oxidation status of plant sterols (i.e., concentrations of plasma oxyphytosterols). Therefore, in the Framingham Offspring Study cohort, we measured plasma oxyphytosterol concentrations in 144 patients with documented CVD and/or more than 50% carotid stenosis and 383 matched controls. We analyzed plasma oxyphytosterol concentrations by GC/MS/MS and performed conditional logistic regression analysis to determine associations between plasma plant sterol or oxyphytosterol concentrations and CVD status. We found that higher total cholesterol (TC)-standardized campesterol concentrations [odds ratio (OR): 2.36; 95% CI: 1.60, 3.50] and higher sitosterol concentrations (OR: 1.47; 95% CI: 1.09, 1.97) were significantly associated with increased CVD risk, as in the earlier study. However, the sum of absolute oxyphytosterol concentrations (OR: 0.99; 95% CI: 0.81, 1.21) and the sum of TC-standardized oxyphytosterol concentrations (OR: 0.98; 95% CI: 0.80, 1.19) were not associated with an increased CVD risk. Results were comparable for individual absolute and TC-standardized oxycampesterol and oxysitosterol concentrations. Plasma nonoxidized TC-standardized sitosterol and campesterol concentrations showed weak or no correlations with oxyphytosterol concentrations, while all individual plasma concentrations of oxyphytosterol correlated with each other. In conclusion, circulating plasma oxyphytosterols are not associated with CVD risk in the Framingham Offspring Study.

Abstract Background Lipid metabolism imbalance has been recognized as one of the major drivers of impaired glucose metabolism in the context of type 2 diabetes mellitus (T2DM), the rates of which are steadily increasing worldwide. Impaired glucose regulation (IGR) plays a vital role in the prevention and treatment of T2DM. The goal of this study was to further clarify whether the combination of plant sterols (PS) and omega-3 fatty acids yields any synergistic effect that enhances the prevention and treatment of IGR. Methods A total of 200 participants were randomized to receive PS and omega-3 fatty acids (n = 50), PS alone (n = 50), omega-3 fatty acids alone (n = 50), or placebo soy bean powder plus placebo capsules (n = 50) for 12 weeks. Patient characteristics including body composition, blood pressure, glucose metabolism (Fasting plasma glucose (FPG), fasting insulin (FINS), glycosylated hemoglobin (HbA1c), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)), lipid metabolism (TG, TC, HDL-C, LDL-C) and inflammatory factors (Hs-CRP, IL-6) were all monitored in these IGR individuals. Results Compared to the placebo group, the group receiving the combined intervention exhibited significantly decreased TG, HDL-C, FBG, HOMA-IR and HbA1c. Omega-3 fatty acids alone were associated with significant reductions in waistline, TG, FBG, HOMA-IR and Hs-CRP. PS alone was only associated with decreased TG and Hs-CRP. No interventions produced significant changes in body weight, BMI, blood pressure, FINS, body fat percentage, visceral fat rating, TC, LDL-C or IL-6. Conclusions In summary, this study has demonstrated for the first time that PS, omega-3 fatty acids or the combination thereof significantly improved inflammation, insulin resistance, as well as glucose and lipid metabolism in IGR individuals. These findings may provide a scientific basis for the development of nutritional products incorporating PS and omega-3 fatty acids, and also for the development of nutritional supplement strategies aimed at preventing the development of disease in the IGR population.

There are scarce data on plant sterols (PS) and gut microbiota relationship. The purpose of this study is to compare the interaction between PS and gut microbiota through in vitro colonic fermentation studies using a validated system (TIM-2) with a PS-enriched dose (∼2 g/day) from two sources (food PS-source ingredient and commercial standard) using microbiota from lean and obese populations. Fecal sterols, short chain fatty acids (SCFA) and microbiota composition were determined by GC/MS, IEC, and 16S-sequencing, respectively.PS-feeding decreased coprostanol and ethylcoprostanol concentration and increased the production of acetate and butyrate (mainly with lean microbiota). In addition, the PS-enrichment dose increased the proportion of some genera from phylum Firmicutes with lean and obese microbiota.The results obtained suggest that the gut microbiota preferably use PS as a substrate. In addition, PS-enrichment dose had no effect on the production of SCFA but modified the microbial profile of lean and obese populations.

The effect of the incorporation of key enzymes of the lipidic metabolism to the INFOGEST (Improving health properties of food by sharing the knowledge on the digestive process) digestion method on plant sterol (PS) bioaccessibility is evaluated in a PS-enriched wholemeal rye bread. The assayed conditions were: (i) INFOGEST method; (ii) INFOGEST+gastric lipase (GL) (60 U/mL gastric digesta); and (iii) INFOGEST+GL+cholesterol esterase (CE) (0.075 U/mL intestinal digesta). The contents of PSs were determined in bioaccessible fractions after saponification and derivatization into trimethylsilylethers and were then analyzed by gas chromatography-mass spectrometry (for identification purposes) and gas chromatography-flame ionization detection (for quantification). The identified PSs from the PS-ingredient and rye flour were: campesterol, campestanol, stigmasterol, b-sitosterol, sitostanol, D5-avenasterol, D5,24-stigmastadienol, D7-stigmastenol and D7-avenasterol. The incorporation of the lipidic enzymes slightly reduced the bioaccessibility of the total (from 23.2 to 17.6–18.2%) and individual PS (from 22.6–57.7 to 17.3–44%). In addition, no differences in bioaccessibility were detected when GL or GL+CE were used. The largest bioaccessibility values were shown for D5-avenasterol and D7-avenasterol, regardless of the conditions assayed. In conclusion, the use of GL and CE means a closer approach to in vivo conditions, and we propose their inclusion in the INFOGEST model for the evaluation of the bioaccessibility of sterols and other lipid bioactive compounds.

Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder that is characterized by hyper absorption of plant sterols from the intestinal mucosa leading to toxic levels in the blood. Four patients of age ranging from 11 to 29 years presented to the outpatient department with clinical features of hemolytic anemia. There were no features of hypercholesterolemia in any of the patients. Peripheral smear examination of all four patients showed stomatocytes and macrothrombocytopenia. Qualitative testing for plant sterols was performed in one case. Next generation sequencing revealed a compound heterozygous mutation in ABCG5 gene (c.1222C>T and c.1255C>T) in one case and homozygous mutations in ABCG5 gene (c.727C>T), (c.332G>A (p.G111E)), (c.1222C>T) in the other three cases. Ezetimibe (10 mg/day) was administered in one case, with complete resolution of symptoms. All patients were advised a low plant sterol diet and regular monitoring of hemoglobin and lipid profile. Our cases highlight a rare but important cause of hemolytic anemia that can be suspected from careful peripheral blood examination but only conclusively established by molecular genetic diagnosis. [ABSTRACT FROM AUTHOR]

This study evaluates the impact of two plant sterol (PS) enriched fruit beverages (0.6 g /100 ml), without (MfB) or with GOS (MfB-G) (1.2 g/100 ml) on the resistance against oxidative stress induced by non-conventional (cholesterol oxidation products (COPs)) and conventional (H2O2) oxidant compounds, as well as their impact on C. elegans longevity. Nematodes fed with both beverages (0.005–0.25%, v/v) showed similar improved oxidative stress resistance against COPs and H2O2. This effect was dependent on daf-16 transcription factor, although GOS showed an additional beneficial effect independent to daf-16. In addition, both beverages extended nematode lifespan, independently of the presence of GOS. Longevity assays using daf-16 and daf-2 mutant strains revealed that the observed effect was potentially linked to the insulin-IGF-1 pathway. These results provide new in vivo evidence for the potential use of PS enriched fruit beverages in the prevention of oxidative stress underlying many diseases.