Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis.

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.

Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8.

Classical lipid transporters are suggested to modulate cellular vitamin D uptake. This study investigated the vitamin D levels in serum and tissues of mice deficient in SR-B1 (Srb1-/-), CD36 (Cd36-/-) and ABC-G5/G8 (Abcg5/g8-/-) and compared them with corresponding wild-type (WT) mice. All mice received triple-deuterated vitamin D3 (vitamin D3-d3) for six weeks. All knockout mice vs. WT mice showed specific alterations in their vitamin D concentrations. Srb1-/- mice had higher levels of vitamin D3-d3 in the serum, adipose tissue, kidney and heart, whereas liver levels of vitamin D3-d3 remained unaffected. Additionally, Srb1-/- mice had lower levels of deuterated 25-hydroxyvitamin D3 (25(OH)D3-d3) in the serum, liver and kidney compared to WT mice. In contrast, Cd36-/- and WT mice did not differ in the serum and tissue levels of vitamin D3-d3, but Cd36-/- vs. WT mice were characterized by lower levels of 25(OH)D3-d3 in the serum, liver and kidney. Finally, Abcg5/g8-/- mice tended to have higher levels of vitamin D3-d3 in the serum and liver. Major alterations in Abcg5/g8-/- mice were notably higher levels of 25(OH)D3-d3 in the serum and kidney, accompanied by a higher hepatic mRNA abundance of Cyp27a1 hydroxylase. To conclude, the current data emphasize the significant role of lipid transporters in the uptake, tissue distribution and activation of vitamin D.

Interindividual variability in the cholesterol-lowering effect of supplementation with plant sterols or stanols.

Low-density lipoprotein cholesterol (LDL-C) plays a causal role in atherosclerosis. One way to reduce LDL-C levels is to inhibit cholesterol absorption. Plant sterols and stanols compete with cholesterol for absorption in the intestine and induce an average decrease in LDL-C by 5% to 15% in a dose-dependent manner, but not in all individuals. This review focuses on the interindividual variability in response to dietary supplementation with plant sterols and stanols. Dietary plant sterols and stanols have no significant effects on LDL-C in substantial numbers of individuals. Higher responses, in absolute value and percentage of LDL-C, are observed in individuals with higher cholesterol absorption and a lower rate of cholesterol synthesis. Some data provide evidence of the influence of genetics on the response to plant sterols and stanols. Further studies in large populations are required to extend these conclusions about genetic influences.

Agaricus brasiliensis (sun mushroom) affects the expression of genes related to cholesterol homeostasis.

PURPOSE: The sun mushroom (Agaricus brasiliensis) is considered a major source of bioactive compounds with potential health benefits. Mushrooms typically act as lipid-lowering agents; however, little is known about the mechanisms of action of A. brasiliensis in biological systems. This study aimed to determine the underlying mechanism involved in the cholesterol-lowering effect of A. brasiliensis through the assessment of fecal and serum lipid profiles in addition to gene expression analysis of specific transcription factors, enzymes, and transporters involved in cholesterol homeostasis. METHODS: Twenty-four albino Fischer rats approximately 90 days old, with an average weight of 205 g, were divided into four groups of 6 each and fed a standard AIN-93 M diet (C), hypercholesterolemic diet (H), hypercholesterolemic diet +1 % A. brasiliensis (HAb), or hypercholesterolemic diet +0.008 % simvastatin (HS) for 6 weeks. Simvastatin was used as a positive control, as it is a typical drug prescribed for lipid disorders. Subsequently, blood, liver, and feces samples were collected for lipid profile and quantitative real-time polymerase chain reaction gene expression analyses. RESULTS: Diet supplementation with A. brasiliensis significantly improved serum lipid profiles, comparable to the effect observed for simvastatin. In addition, A. brasiliensis dietary supplementation markedly promoted fecal cholesterol excretion. Increased expression of 7α-hydroxylase (CYP7A1), ATP-binding cassette subfamily G-transporters (ABCG5/G8), and low-density lipoprotein receptor (LDLR) was observed following A. brasiliensis administration. CONCLUSIONS: Our results suggest that consumption of A. brasiliensis improves the serum lipid profile in hypercholesterolemic rats by modulating the expression of key genes involved in hepatic cholesterol metabolism.