Phytosterols and human lipid metabolism: efficacy,safety, and novel foods

Plant sterols have been known for several decades to cause reductions in plasma cholesterol concentrations. These plant materials have been granted a conditional health claim in the United States regarding their effects in the prevention of cardiovascular disease and are being sold in functional foods in several countries in Europe as well as in the United States and Australia. It is generally suggested that daily consumption of ∼2 g of plant sterols can lower cholesterol concentrations as part of a dietary prevention strategy. However, phytosterols have been added and tested for their cholesterol-lowering effects mainly in spreads. Consumption of these high-fat foods seemingly flies in the face of current recommendations for the promotion of heart health, which suggest lowering total fat and energy intake to maintain weight. Hence, new food formulations are being evaluated using phytosterols incorporated into low-fat and reduced-fat food items. The purpose of this review is to examine the cholesterol-lowering efficacy of plant sterols, focusing on novel food applications, their mechanism of action, and safety. These novel food formulations include new solubilization processes that lead to improved uses for plant sterols, as well as new foods into which phytosterols have been incorporated, such as breads, cereals, and beef. Such new foods, and formulations should pave the way for greater use of phytosterols in heart health promotion, increasing the longer-term potential for the creation of innovative functional foods containing plant sterols and their derivatives.     

Phytosterols,Cholesterol Absorption and Healthy Diets

The purpose of this review is to outline the emerging role of dietary phytosterols in human health. Dietary saturated fat, cholesterol and fiber are currently emphasized in the reduction of low-density lipoprotein cholesterol levels. However, other dietary components such as phytosterols may have equivalent or even larger effects on circulating cholesterol and need further study with respect to the potential for coronary heart disease risk reduction. Phytosterol effects were not considered in classic fat-exchange clinical trials and may account for some of the differences attributed to the food fats studied. Phytosterols reduce cholesterol absorption while being poorly absorbed themselves and the effects can be studied in human subjects in single-meal tests using stable isotopic tracers. Because phytosterols are insoluble and biologically inactive when purified, careful attention needs to be given to ensuring that commercial supplement products are rendered bioavailable by dissolution in fat or by emulsification. Recent work shows that phytosterols in natural food matrices are also bioactive. The retention of phytosterols during food manufacturing and the use of foods with high phytosterol content may constitute an alternative to the use of supplements.     

The Digestibility and Accumulation of Dietary Phytosterols in Atlantic Salmon (<Emphasis Type="Italic">Salmo salar</Emphasis> L.) Smolt Fed Diets with Replacement Plant Oils

Phytosterols occur in high concentration in canola (Brassica napus L.) and other vegetable oils such as from the borage plant Echium (Echium plantagineum L.). We investigated if Atlantic salmon (Salmo salar) digest and accumulate dietary phytosterols in significant amounts in muscle and liver. Phytosterols are lipid soluble, lower cholesterol and reduce the risk of coronary heart disease in humans. We aimed to determine if fatty fish, such as salmon, can be used as a delivery source of this functional food component. Three diets containing canola oil (CO), Echium oil (EO) and fish oil (FO) were fed to Atlantic salmon smolt over 9 weeks. The digestibility of natural abundances of phytosterols by Atlantic salmon was poor compared to cholesterol. However, phytosterols accumulated in liver and muscle of fish. Significantly increased concentrations of 24-methylenecholesterol, campesterol, beta-sitosterol and total phytosterol occurred in livers of EO fed fish compared to FO fed fish. Campesterol concentrations increased in CO fed fish compared to the FO fed fish. We demonstrated that natural abundances of dietary phytosterols are digested by and accumulated in liver and white muscle of Atlantic salmon smolt. However, phytosterol levels in salmon muscle will not be a major source of phytosterols in human diets and would not be expected to significantly effect human cardiovascular health.     

Cholesterol‐lowering effect of plant sterols

Intake of plant sterols (4‐desmethyl sterols, phytosterols) reduces cholesterol absorption and lowers serum total and LDL cholesterol levels in humans. The use of dietary plant sterol regimens for lowering elevated serum cholesterol values has recently gained much interest, especially after the commercial introduction of margarines containing plant stanols esterified with fatty acids. The solubility of free, crystalline plant sterols and stanols in edible oils and fats is low, limiting their use especially in fat‐containing food. By esterifying of, e.g., plant stanols with fatty acids derived from a vegetable oil fatty acid ester of plant stanols with fat‐like properties are obtained. These fat‐soluble forms of plant stanols provide a technically feasible way of introducing the adequate daily amount of plant sterol into foods for optimal reduction of the cholesterol absorption, without changing the taste of the finished product. The cholesterol‐lowering effect of plant stanol esters has been extensively studied. Plant stanol esters effectively restrict the absorption of both dietary and biliary cholesterol causing plant stanol specific reductions in serum total and LDL cholesterol levels of up to 10% and 14%, respectively. Serum HDL cholesterol and triglyceride levels are not affected. The cholesterol‐lowering effect of plant stanol esters complements the beneficial effects of a healthy diet and cholesterol medication.     

Dietary fibers and cardiometabolic diseases

The high prevalence of cardiovascular disease (CVD) is largely attributable to the contemporary lifestyle that is often sedentary and includes a diet high in saturated fats and sugars and low ingestion of polyunsaturated fatty acids (PUFAs), fruit, vegetables, and fiber. Experimental data from both animals and humans suggest an association between increased dietary fiber (DF) intakes and improved plasma lipid profiles, including reduced low density lipoprotein cholesterol (LDL-C) concentrations. These observations underline that the intake of DF may protect against heart disease and stroke.     

A comparison of the effect of medium- vs. long-chain triglycerides on the <Emphasis Type="Italic">in vitro</Emphasis> solubilization of cholesterol and/or phytosterol into mixed micelles

Despite clinical evidence of the cholesterol-lowering effects of phytosterols, the exact mechanisms involved are still unclear. Displacement of cholesterol by phytosterols from mixed micelles, which is due to their greater hydrophobicity, is one of the hypotheses for the lumenal effects contributing to the reduction of intestinal cholesterol absorption. In this study a dynamic in vitro lipolysis method was used to examine the solubilization behavior of cholesterol and/or phytosterols during lipolysis to probe the efficacy of cholesterol displacement from mixed micelles by phytosterols. The effects of lipid chain length on sterol solubilization were studied by using microcrystalline suspensions containing 17% phytosterol or cholesterol, formulated in long-chain TG (LCT) and medium-chain TG (MCT). When digesting cholesterol suspended in LCT, the entire cholesterol dose was incorporated into the micellar phase. For the cholesterol formulation suspended in MCT, 50.3% of the initial dose was recovered in the micelles. Under the respective conditions, we observed lower solubilization of phytosterols than of cholesterol (roughly fourfold). Only 25% of the initial phytosterol dose was solubilized from suspensions formulated with LCT, and 13% was solubilized from MCT formulations. Co-administration of phytosterol and cholesterol suspensions showed a significant reduction of cholesterol solubilization, particularly when dosed in MCT, with ≈25% of the cholesterol dose solubilized. Insignificant amounts of cholesterol were displaced by phytosterols when cholesterol was presolubilized in the mixed micelles. The results show that, compared with LCT, mixed micelles containing MCT lipolysis products have a reduced solubilizing capacity for cholesterol, which adds to the effectiveness of the phytosterols in displacing cholesterol. This suggests potential benefits of using medium chain length lipids in cholesterol-lowering phytosterol products.     

Interaction between dietary proteins and lipids in the regulation of serum and liver lipids in the rabbit. Effect of fish protein

Purified diets varying in dietary protein, namely casein (CA), soy protein (SP), fish protein (FP), and lipid origin (corn oil (CN), coconut oil (CO)) were fed to rabbits to evaluate the effects of protein and fat source, as well as protein-lipid interactions, on serum total, lipoprotein and hepatic lipid levels. Dietary proteins and lipids exerted a separate effect on serum total cholesterol (C), very low-density lipoprotein cholesterol (VLDL-C), and low-density lipoprotein cholesterol to high density lipoprotein cholesterol (LDL-C/HDL-C) ratio. Hence, CA increased serum cholesterol compared to SP, while coconut oil enhanced serum and VLDL-C, and decreased LDL-C/HDL-C compared to corn oil. Dietary proteins interacted with dietary lipids to modulate HDL-C levels. Thus, FP maintained a high level of HDL-C regardless of lipid origin, compared to CA and SP whose HDL-C levels were decreased by corn oil, compared to coconut oil. A dietary protein-lipid interaction was also observed in the regulation of liver cholesterol levels. Coconut oil, compared to corn oil, decreased liver cholesterol in rabbits fed FP, whereas hepatic cholesterol concentration was unaltered by dietary lipid source in CA- and SP-fed rabbits. These results demonstrate that dietary proteins act synergistically with dietary lipids to regulate cholesterol metabolism in the rabbit. This work was presented in part at the 74th Annual FASEB meeting held in Washington, D.C., April 1–5, 1990.     

The twisted tale of saturated fat

Recent research results mandate a careful re‐evaluation of the widespread belief that dietary saturated fat is harmful. Specifically, multiple recent reports find no association between dietary saturated fat intakes and cardiovascular disease (CVD). There is, however, a consistent pattern of increased risk for both CVD and type‐2 diabetes associated with increased levels of saturated fatty acids (SFA) in circulating lipids. This raises the important question as to what contributes to increased levels of saturated fat in the blood? Whereas dietary intake of saturated fats and serum levels of SFA show virtually no correlation, an increased intake of carbohydrate is associated with higher levels of circulating SFA. This leads to the paradoxical conclusion that dietary saturated fat is not the problem; rather it's the over‐consumption of carbohydrate relative to the individual's ability to metabolize glucose without resorting to de novo lipogenesis. From this perspective, insulin resistant states like metabolic syndrome and type‐2 diabetes can be viewed as carbohydrate intolerance, in which a high carbohydrate intake translates to increased serum SFA and therefore increased risk.     

Date Palm Fruit (Phoenix dactylifera): Effects on Vascular Health and Future Research Directions

Cardiovascular disease is a leading cause of death globally, presenting an immense public and economic burden. Studies on cardioprotective foods and their bioactive components are needed to address both personal and public health needs. Date fruit is rich in polyphenols, particularly flavonoids, certain micronutrients, and dietary fiber, which can impact vascular health, and have the potential to attenuate vascular disease in humans. Data from in vitro and animal studies report that consumption of date fruit or extracts can modulate select markers of vascular health, particularly plasma lipid levels including triglycerides and cholesterol, indices of oxidative stress and inflammation, but human data is scant. More investigation is needed to better characterize date polyphenols and unique bioactive compounds or fractions, establish safe and effective levels of intake, and delineate underlying mechanisms of action. Implementing scientific rigor in clinical trials and assessment of functional markers of vascular disease, such as flow-mediated dilation and peripheral arterial tonometry, along with gut microbiome profiles would provide useful information with respect to human health. Emerging data supports the notion that intake of date fruit and extracts can be a useful component of a healthy lifestyle for those seeking beneficial effects on vascular health.     

Low-Density Lipoprotein Cholesterol/High-Density Lipoprotein Cholesterol Ratio and Carotid Intima-Media Thickness: A Cohort Study in China

Low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio may carry additional information and has been suggested as a better predictor for atherosclerosis progression and cardiovascular disease (CVD) than LDL-C and HDL-C alone. Therefore, we aim to explore the association between LDL-C/HDL-C ratio and high carotid intima-media thickness (CIMT) risk in a large Cohort in Beijing, China. This cohort study included 13,612 adults without high CIMT at first entry and who attended the baseline examination and at least one follow-up annual examination between 2009 and 2016. We used multivariable Cox regression to estimate hazard ratios (HR) with their 95% confidence intervals (CI) for the association between LDL-C/HDL-C ratio and risk of high CIMT. During 37,912 person-years of follow-up, 1996 (1268 men and 728 women) developed high CIMT. Compared with the first quartile of LDL-C/HDL-C ratio, the risk of high CIMT was significantly increased for the fourth quartile of LDL-C/HDL-C ratio (HR = 1.51, 95% CI: 1.29–1.78). We observed a significant association between LDL-C/HDL-C ratio and high CIMT risk comparing LDL-C/HDL-C ratio >2.78 with LDL-C/HDL-C ratio ≤2.78 and significant dose–response relationship between LDL-C/HDL-C ratio and risk of high CIMT. The restricted cubic spline showed a significant nonlinear association between LDL-C/HDL-C ratio and the risk of high CIMT (p_{non-linearity} = 0.009). We identify a significant association between LDL-C/HDL-C ratio and the risk of high CIMT in the Chinese Cohort study. Future studies are needed to evaluate the effectiveness of reducing LDL-C/HDL-C ratio treatment on the development of high CIMT.     

Genetic Risk Scores for Maternal Lipid Levels and Their Association with Preterm Birth

Maternal lipid profiles are associated with risk for preterm birth (PTB), although the lipid component and effect size are inconsistent between studies. It is also unclear whether these associations are the result of excessive changes in lipid metabolism during pregnancy or genetic variability in genes controlling basal lipid metabolism. This study investigates the association between genetic risk scores (GRS) for four lipid components (high-density lipoprotein [HDL-C], low-density lipoprotein [LDL-C], triacylglycerols [TAG], and total cholesterol [TC]) with risk for PTB. Subjects included 954 pregnant women from California for whom second trimester serum samples were available, of which 479 gave birth preterm and 475 gave birth at term. We genotyped 96 single-nucleotide polymorphisms, which were selected from genome-wide association studies of lipid levels in adult populations. Lipid-specific GRS were constructed for HDL-C, LDL-C, TAG, and TC. The associations between GRS and PTB were analyzed using logistic regression. A higher HDL-C GRS was associated with increased risk for PTB overall and spontaneous PTB. Higher TAG and TC GRS were associated with decreased risk for PTB overall and spontaneous PTB. This study identifies counter-intuitive associations between lipid GRS and spontaneous PTB. Further replication studies are needed to confirm these findings, but they suggest that our current scientific understanding of the relationship between lipid metabolism, PTB, and genetics is incomplete.     

Hyperphosphataemia is associated with the diabetes-related cardiovascular risk factors

The serum phosphorus level is recently considered as one of the foretelling markers for the severity of cardiovascular diseases (CVD). We therefore investigated whether the serum phosphorus level in the diabetic patients against healthy individuals could act as a possible marker for identification of vulnerability to cardiovascular disease. One hundred and thirty two human subjects were involved in the study among which one hundred and four subjects are CVD patients and twenty eight were healthy individuals. The levels of the lipid profile and the glycemic status were significantly increased in the patients than those of the control subjects (Fasting glucose, FS=8.3 ± 0.3 vs. 6.1 ± 0.0 mmol/L; blood glucose 2 h after breakfast (STAB)=12.0 ± 0.5 vs. 8.5 ± 0.7, mmol/L; HbA1c (%),6.7 ± 0.2 vs. 5.4 ± 0.3; and Total cholesterol (TC)=189 ± 4.0 vs. 162 ± 7.0; low density lipoprotein cholesterol (LDL-C), 111 ± 3.8 vs. 96 ± 5.0; triacyglycerol (TG), 202 ± 9.0 vs. 118 ± 5.3 mg/dL, respectively. The serum phosphorus level was significantly increased in CVD patients (mg/dL, patient vs. control, 5.1 ± 0.10 vs. 3.7 ± 0.1). Simple regression analyses revealed a highly significant positive correlation between serum phosphorus and TC, TG and FG. Thus the results demonstrate that the serum phosphorus level might be another parameter which is closely associated with diabetes and could also be used as a possible marker for the risk of CVD.     

Genetic Variation in <Emphasis Type="Italic">ABC G5/G8</Emphasis> and <Emphasis Type="Italic">NPC1L1</Emphasis> Impact Cholesterol Response to Plant Sterols in Hypercholesterolemic Men

ATP-binding cassette hetero-dimeric transporters G5 and G8 (ABCG5/G8) have been postulated to mediate intestinal cholesterol efflux, whereas Niemann-Pick C1 Like 1 (NPC1L1) protein is believed to be essential for intestinal cholesterol influx. The individual or combined genetic markers, such as single nuclear polymorphisms (SNPs), of these two transporter genes may explain inter-individual variations in plasma cholesterol response following plant sterol (PS) intervention. The present study was aimed at investigating the association between ABCG5/G8 and NPC1L1 genotype SNPs with sterol absorption and corresponding plasma concentrations. The study used a 4-week crossover design with 82 hypercholesterolemic men characterized by high vs. low basal plasma PS concentrations consuming spreads with or without 2 g/day of PS. For the ABCG8 1289 C > A (T400 K) polymorphism, the A allele carriers with high basal plasma PS concentrations demonstrated a 3.9-fold greater reduction (p < 0.05) in serum low density lipoprotein cholesterol (LDL-C) than their low basal plasma PS counterparts. For the NPC1L1 haplotype of 872 C > G (L272L) and 3929 G > A (Y1291Y), individuals carrying mutant alleles showed a 2.4-fold greater (p < 0.05) reduction in LDL-C levels, compared to wild type counterparts. Results suggest that genetic and metabolic biomarkers together may predict inter-individual lipid level responsiveness to PS-intervention, and thus could be useful in devising individualized cholesterol lowering strategies.     

Beneficial effects of vaccenic acid on postprandial lipid metabolism and dyslipidemia: Impact of natural trans‐fats to improve CVD risk

Abnormal non‐fasting (postprandial) lipid metabolism has been recognized as a significant contributor to dyslipidemia and cardiovascular disease (CVD) risk. Clinically, impaired metabolism of lipoproteins following a meal (e.g. chylomicrons) has been demonstrated in a number of chronic diseases, including obesity, insulin resistance, as well as type 1 and 2 diabetes. Given the proposed effects of dietary trans fat to contribute to a lipid profile that increases CVD risk, there has been a public health campaign in many countries to eliminate these fatty acids from the food supply. In contrast, our group has recently reported novel lipid‐lowering benefits of a major naturally‐occurring trans fatty acid vaccenic acid (VA, shorthand lipid name 18:1 trans‐11), in an animal model of dyslipidemia and the metabolic syndrome. Studies to date have shown that dietary supplementation of VA effectively reduces not only fasting lipids, but also postprandial triacylglycerol and chylomicron concentrations in obese JCR:LA‐cp rats. Evidence from animal studies to date suggest that VA may down‐regulate hepatic fatty acid synthesis and directly influence lipogenesis in the intestine. The discovery of new bioactive properties of VA is supported by clinical studies which have provided increased momentum for industry applications. In this review we summarize the emerging beneficial view of natural trans fats that have distinct and differential properties compared to those synthetically produced in partially hydrogenated vegetable oils (PHVO), with a particular focus on fasting and postprandial lipid metabolism in CVD risk.     

How good is the evidence for the lipid hypothesis?

The evidence for the lipid hypothesis is weak. After 20 years of follow‐up, the Nurses Health Study, a prospective cohort study, was no longer able to demonstrate an association between intakes of saturated fat and risk of developing coronary heart disease. Randomised controlled trials with statins have shown that lowering LDL‐cholesterol levels by 23% can reduce the risk of developing cardiovascular disease but reducing saturated fat can only reduce cholesterol levels by 10%. This issue can only be resolved by carrying out randomised controlled dietary trials with CVD endpoints. Although there are scientific difficulties standing in the way of such trials, it is the opinion of this author that these can be overcome. Whether there is the political will to fund them is another matter although some of the money currently spent on prospective cohort studies would be far better spent on randomised controlled trials.     

Effects of cholestyramine and squalene feeding on hepatic and serum plant sterols in the rat

Hepatic and serum phytosterol concentrations were compared in the rat under basal conditions and during activated cholesterol and bile acid production due to squalene and cholestyramine feeding. Both treatments consistently decreased hepatic and serum levels of sitosterol and campesterol and, unlike esterified cholesterol, esterified plant sterols were not increased in liver during squalene feeding. Serum levels of phytosterols were decreased quite proportionately to those in the liver. The hepatic levels of sitosterol and campesterol closely correlated with each other, but not with cholesterol levels. The percentage esterification of both phytosterols was lower than that of cholesterol. The results indicate that activation of hepatic sterol production leads to depletion of hepatic plant sterols. It is suggested that poor esterification of plant sterols may contribute to this decrease.     

A High Legume Low Glycemic Index Diet Improves Serum Lipid Profiles in Men

Clinical studies have shown that fiber consumption facilitates weight loss and improves lipid profiles; however, the beneficial effects of high fermentable fiber low glycemic index (GI) diets under conditions of weight maintenance are unclear. In the Legume Inflammation Feeding Experiment, a randomized controlled cross-over feeding study, 64 middle-aged men who had undergone colonoscopies within the previous 2 years received both a healthy American (HA) diet (no legume consumption, fiber consumption = 9 g/1,000 kcal, and GI = 69) and a legume enriched (1.5 servings/1,000 kcal), high fiber (21 g/1,000 kcal), low GI (GI = 38) diet (LG) in random order. Diets were isocaloric and controlled for macronutrients including saturated fat; they were consumed each for 4 weeks with a 2–4 week break separating dietary treatments. Compared to the HA diet, the LG diet led to greater declines in both fasting serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) (P < 0.001 and P < 0.01, respectively). Insulin-resistant (IR) subjects had greater reductions in high density lipoprotein cholesterol (HDL-C; P < 0.01), and triglycerides (TAG)/HDL-C (P = 0.02) after the LG diet, compared to the HA diet. Insulin-sensitive (IS) subjects had greater reductions in TC (P < 0.001), LDL-C (P < 0.01), TC/HDL-C (P < 0.01), and LDL-C/HDL-C (P = 0.02) after the LG diet, compared to the HA diet. In conclusion, a high legume, high fiber, low GI diet improves serum lipid profiles in men, compared to a healthy American diet. However, IR individuals do not achieve the full benefits of the same diet on cardiovascular disease (CVD) lipid risk factors.     

Techniques for the extraction of phytosterols and their benefits in human health: a review

This review summarizes the information on the health-promoting effects of phytosterols and the techniques for their extraction. The extraction and analysis processes of phytosterols are complex and have not been fully established. Phytosterols have significant roles in the areas of foods, nutrition, pharmaceuticals, and cosmetics. Free phytosterols extracted from plant sources are widely used in fortified foods and dietary supplements. Most phytosterols are extracted from plant matrices using organic solvents which are health and environmental hazards. However, the application of supercritical fluid in the extraction of phytosterols has offered a promising green technology in overcoming the limitations of conventional extraction.     

Efficacy and safety of turmeric and curcumin in lowering blood lipid levels in patients with cardiovascular risk factors: a meta-analysis of randomized controlled trials

Background

Dyslipidemia is an important and common cardiovascular risk factor in the general population. The lipid-lowering effects of turmeric and curcumin are unconfirmed. We performed a meta-analysis to assess the efficacy and safety of turmeric and curcumin in lowering blood lipids in patients at risk of cardiovascular disease (CVD).

Methods

A comprehensive literature search was conducted on PubMed, Embase, Ovid, Medline and Cochrane Library databases to identify randomized controlled trials (published as of November 2016) that assessed the effect of turmeric and curcumin on blood lipid levels including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Pooled standardized mean difference (SMD) with 95% confidence interval (CI) was used to assess the effect.

Results

The analysis included 7 eligible studies (649 patients). Turmeric and curcumin significantly reduced serum LDL-C (SMD = ?0.340, 95% confidence interval [CI]: ?0.530 to ?0.150, P < 0.0001) and TG (SMD = ?0.214, 95% CI: ?0.369 to ?0.059, P = 0.007) levels as compared to those in the control group. These may be effective in lowering serum TC levels in patients with metabolic syndrome (MetS, SMD = ?0.934, 95% CI: ?1.289 to ?0.579, P < 0.0001), and turmeric extract could possibly have a greater effect on reducing serum TC levels (SMD = ?0.584, 95% CI: ?0.980 to ?0.188, P = 0.004); however, the efficacy is yet to be confirmed. Serum HDL-C levels were not obviously improved. Turmeric and curcumin appeared safe, and no serious adverse events were reported in any of the included studies.

Conclusions

Turmeric and curcumin may protect patients at risk of CVD through improving serum lipid levels. Curcumin may be used as a well-tolerated dietary adjunct to conventional drugs. Further research is required to resolve uncertainties related to dosage form, dose and medication frequency of curcumin.