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To investigate the cholesterol-lowering effectiveness of a phytosterol/α-lipoic acid (PS/αLA) therapy, thirty-two male Zucker rats were randomly assigned to 1 of 4 diets for 30 days: (i) high fat diet (HF, 40% energy from fat); (ii) HF diet supplemented with 3% phytosterols; (iii) HF diet supplemented with 0.25% αLA; or (iv) HF diet supplemented with PS (3%) and αLA (0.25%, PS/αLA). Compared with the HF diet, combination PS/αLA proved more effective in reducing non-HDL cholesterol (−55%) than either the PS (−24%) or the αLA (−25%) therapies alone. PS supplementation did not affect LDL particle number, however, αLA supplementation reduced LDL particle number when supplemented alone (−47%) or in combination with PS (−54%). Compared with the HF-fed animals, evidence of increased HDL-particle number was evident in all treatment groups to a similar extent (21–22%). PS-mediated interruption of intestinal cholesterol absorption was evident by increased fecal cholesterol loss (+52%) and compensatory increase in HMG-CoA reductase mRNA (1.6 fold of HF), however, αLA supplementation did not affect fecal cholesterol loss. Hepatic mRNA and protein expression patterns suggested that αLA modulated multiple aspects of cholesterol homeostasis including reduced synthesis (HMG-CoA reductase mRNA, 0.7 fold of HF), reduced bile acid synthesis (CYP7a1 expression, 0.17 of HF), and increased cholesterol clearance (reduced PCSK9 mRNA, 0.5 fold of HF; increased LDLr protein, 2 fold of HF). Taken together, this data suggests that PS and αLA work through unique and complementary mechanisms to provide a superior and more comprehensive cholesterol lowering response than either therapy alone. [ABSTRACT FROM AUTHOR]

Background: In utero exposure to excessive cholesterol has been shown to increase fetal plasma cholesterol concentration and predispose adult offspring to cardiovascular disease (CVD) risk. Because lipid-lowering drugs are contraindicated during pregnancy, natural cholesterol-lowering compounds may be a safe and effective alternative to reduce CVD risk in offspring born to hypercholesterolemic mothers. Objective: This study used the hypercholesterolemic apolipoprotein E-deficient (apoE-/-) mouse model to test the hypothesis that mothers supplemented with phytosterols during gestation and lactation would produce offspring with a more favorable lipid profile than offspring from unsupplemented mothers, despite having a genetic predisposition toward hypercholesterolemia. Methods: Sixteen female apoE-/- mice were randomly assigned to 2 diets fed throughout the gestation and lactation periods: a cholesterol-enriched diet (CH) (0.15%) or the cholesterol-enriched diet supplemented with phytosterols (CH/PS) (2%). Serum lipids and lipoproteins were measured by enzyme assay and nuclear magnetic resonance spectroscopy, respectively, and liver cholesterol was analyzed by GC. Results: Compared with the CH-fed dams at the end of lactation, phytosterol-supplemented dams displayed lower (P< 0.05) serum total cholesterol (-55%), non-HDL cholesterol (-56%), and LDL cholesterol (-47%), but no change (P> 0.05) in HDL cholesterol and triacylglycerol (TG) concentrations. Pups from phytosterol-fed dams demonstrated lower (P< 0.05) total cholesterol (-25%), non-HDL cholesterol (-25%), LDL cholesterol (-47%), and TGs (-41 %), without any change (P> 0.05) in HDL cholesterol compared with pups from CH-fed dams. Furthermore, compared with pups from CH-fed dams, pups from phytosterol-supplemented dams displayed a lower (P< 0.05) number of total LDL particles (-34%), VLDL particles (-31 %), and HDL particles (-30%). Conclusion: Our results in apoE-/- mice suggest that even under strong genetic predisposition to hypercholesterolemia, pups born to mothers supplemented with phytosterols during gestation and lactation exhibit favorable liver and serum lipid responses compared with pups from unsupplemented mothers. [ABSTRACT FROM AUTHOR]

Background In addition to lowering LDL-C, emerging data suggests that phytosterols (PS) may reduce blood triglycerides (TG), however, the underlying mechanisms are not known. Methods We examined the TG-lowering mechanisms of dietary PS in Syrian golden hamsters randomly assigned to a high fat (HF) diet or the HF diet supplemented with PS (2%) for 6 weeks (n = 12/group). An additional subset of animals (n = 12) was provided the HF diet supplemented with ezetimibe (EZ, 0.002%) as a positive control as it is a cholesterollowering agent with known TG-lowering properties. Results In confirmation of diet formulation and compound delivery, both the PS and EZ treatments lowered (p < 0.05) intestinal cholesterol absorption (24 and 31%, respectively), blood non- HDL cholesterol (61 and 66%, respectively), and hepatic cholesterol (45 and 55%, respectively) compared with the HF-fed animals. Blood TG concentrations were lower (p < 0.05) in the PS (49%) and EZ (68%)-treated animals compared with the HF group. The TGlowering response in the PS-supplemented group was associated with reduced (p < 0.05) intestinal SREBP1c mRNA (0.45 fold of HF), hepatic PPARα mRNA (0.73 fold of HF), hepatic FAS protein abundance (0.68 fold of HD), and de novo lipogenesis (44%) compared with the HF group. Similarly, lipogenesis was lower in the EZ-treated animals, albeit through a reduction in the hepatic protein abundance of ACC (0.47 fold of HF). Conclusions Study results suggest that dietary PS are protective against diet-induced hypertriglyceridemia, likely through multiple mechanisms that involve modulation of intestinal fatty acid metabolism and a reduction in hepatic lipogenesis. [ABSTRACT FROM AUTHOR]

Recent work suggests that plant sterol (PS) consumption may lower triglyceride (TG) concentrations; however, human clinical trial evidence is inconsistent. We associated SNP r5882 in cholesteryl ester transfer protein with changes in TG concentrations following PS consumption (2 g/day for 4 weeks) in a dual-centre, single-blind, randomized, crossover trial. TG concentrations were lowered in homozygotes for the minor G-allele of rs5882 (-0.46 ± 0.13 mmol/L, p = 0.002, n = 10); there was no effect in the A-allele carriers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE-/- mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7βHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options. [ABSTRACT FROM AUTHOR]

Objective: An excessive rise in blood lipids during pregnancy may promote metabolic dysfunction in adult progeny. We characterized how maternal phytosterol (PS) supplementation affected serum lipids and the expression of lipid-regulatory genes in the intestine and liver of newly-weaned apo-E deficient offspring from dams fed a chow diet supplemented with cholesterol (0.15%, CH) or cholesterol and PS (2%) (CH/PS) throughout pregnancy and lactation. Results: Serum lipid concentrations and lipoprotein particle numbers were exacerbated in offspring from cholesterol- supplemented mothers but normalized to chow-fed levels in pups exposed to PS through the maternal diet during gestation and lactation. Compared with the CH pups, pups from PS-supplemented mothers demonstrated higher (p < 0.05) expression of the primary intestinal cholesterol transport protein (Niemann-Pick C1-like 1) and the rate-limiting enzyme in hepatic cholesterol synthesis (HMG-CoAr), suggestive of a compensatory response to restore cholesterol balance. Furthermore, pups from PS-supplemented mothers exhibited a coordinated downregulation (p < 0.05) of several genes regulating fatty acid synthesis including PGC1β, SREBP1c, FAS, and ACC compared with the CH group. These results suggest that maternal PS supplementation during hypercholesterolemic pregnancies protects against aberrant lipid responses in newly-weaned offspring and results in differential regulation of cholesterol and lipid regulatory targets within the enterohepatic loop. [ABSTRACT FROM AUTHOR]