Showing papers on "Sterol published in 2010"
TL;DR: These studies have shown that the traditional roles of HDL and ABC transporters in cholesterol efflux and reverse cholesterol transport are mechanistically linked to antiinflammatory and immunosuppressive functions of HDL.
Abstract: Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries, but the mechanisms linking cholesterol accumulation in macrophage foam cells to inflammation are poorly understood. Macrophage cholesterol efflux occurs at all stages of atherosclerosis and protects cells from free cholesterol and oxysterol-induced toxicity. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of macrophage cholesterol efflux to serum or HDL in macrophage foam cells, but other less efficient pathways such as passive efflux are also involved. Recent studies have shown that the sterol efflux activities of ABCA1 and ABCG1 modulate macrophage expression of inflammatory cytokines and chemokines as well as lymphocyte proliferative responses. In macrophages, transporter deficiency causes increased signaling via various Toll-like receptors including TLR4. These studies have shown that the traditional roles of HDL and ABC transporters in cholesterol efflux and reverse cholesterol transport are mechanistically linked to antiinflammatory and immunosuppressive functions of HDL. The underlying mechanisms may involve modulation of sterol levels and lipid organization in cell membranes.
557 citations
TL;DR: This work shows that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed, and identifies sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for mi R-33–mediated silencing.
Abstract: The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33–mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.
518 citations
TL;DR: A critical role is established for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo in mice lacking microRNA (miR)-33.
Abstract: Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo.
359 citations
TL;DR: The endoplasmic reticulum is the main organelle responsible for regulation of cholesterol synthesis, and careful measurements have shown that the proteins responsible for sterol sensing respond over a very narrow range of cholesterol concentrations to provide very precise, switch-like control over cholesterol synthesis.
325 citations
TL;DR: Sterol metabolites, including cholesterol, 24,25-dihydrolanosterol and oxysterols, strongly participate in the regulation of sterol metabolism via binding to its particular proteins, and hence is deeply involved in regulation of the expression of genes closely related to cholesterol metabolism.
259 citations
TL;DR: Although most fungi in the most speciose clades have ergosterol as a major sterol, sterols are more varied than currently understood, and their distribution supports certain clades of Fungi in current fungal phylogenies.
Abstract: Background
Ergosterol has been considered the “fungal sterol” for almost 125 years; however, additional sterol data superimposed on a recent molecular phylogeny of kingdom Fungi reveals a different and more complex situation.
Methodology/Principal Findings
The interpretation of sterol distribution data in a modern phylogenetic context indicates that there is a clear trend from cholesterol and other Δ5 sterols in the earliest diverging fungal species to ergosterol in later diverging fungi. There are, however, deviations from this pattern in certain clades. Sterols of the diverse zoosporic and zygosporic forms exhibit structural diversity with cholesterol and 24-ethyl -Δ5 sterols in zoosporic taxa, and 24-methyl sterols in zygosporic fungi. For example, each of the three monophyletic lineages of zygosporic fungi has distinctive major sterols, ergosterol in Mucorales, 22-dihydroergosterol in Dimargaritales, Harpellales, and Kickxellales (DHK clade), and 24-methyl cholesterol in Entomophthorales. Other departures from ergosterol as the dominant sterol include: 24-ethyl cholesterol in Glomeromycota, 24-ethyl cholest-7-enol and 24-ethyl-cholesta-7,24(28)-dienol in rust fungi, brassicasterol in Taphrinales and hypogeous pezizalean species, and cholesterol in Pneumocystis.
Conclusions/Significance
Five dominant end products of sterol biosynthesis (cholesterol, ergosterol, 24-methyl cholesterol, 24-ethyl cholesterol, brassicasterol), and intermediates in the formation of 24-ethyl cholesterol, are major sterols in 175 species of Fungi. Although most fungi in the most speciose clades have ergosterol as a major sterol, sterols are more varied than currently understood, and their distribution supports certain clades of Fungi in current fungal phylogenies. In addition to the intellectual importance of understanding evolution of sterol synthesis in fungi, there is practical importance because certain antifungal drugs (e.g., azoles) target reactions in the synthesis of ergosterol. These findings also invalidate use of ergosterol as an indicator of biomass of certain fungal taxa (e.g., Glomeromycota). Data from this study are available from the Assembling the Fungal Tree of Life (AFTOL) Structural and Biochemical Database: http://aftol.umn.edu.
236 citations
TL;DR: Comparison of the azole-bound structures provides insight into the relative binding affinities of human and bacterial P450 enzymes to ketoconazole and fluconazole, which can be useful for the rational design of antifungal compounds and specific modulators of human CYP51.
219 citations
TL;DR: None of the major sterols found in diatoms can be used as an unambiguous diatom biomarker because all of them have been reported as common sterols in other algal groups.
Abstract: Diatoms are one of the most important organisms contributing to aquatic primary productivity and their sterols are frequently used as markers for their presence and abundance. In this study, the sterol composition of >100 diatom cultures was analyzed and its distribution was compared to the diatom phylogeny to identify typical diatom biomarkers. Forty-four sterols were detected, 11 of them being commonly present as major sterols (contributing > 10% to the total sterols). 24-Methylcholesta-5,24(28)-dien-3β-ol is the most common sterol in diatoms, being present in 67% of all cultures analyzed, followed by the Δ 5 sterols, cholest-5-en-3β-ol (cholesterol), 24-methylcholest-5-en-3β-ol, and 24-ethylcholest-5-en-3β-ol. 24-Methylcholesta-5,22E-dien-3β-ol, previously suggested to be specific for diatoms, was only the fifth most common sterol; this sterol was absent in some of the major diatom groups, and high relative concentrations seem to be restricted to pennate diatoms. No sterols are restricted to specific phylogenetic groups of diatoms. Cluster analyses, however, do reveal distinct sterol distributions: Thalassiosirales typically contain high relative abundances of 24-methylcholesta-5,24(28)-dien-3β-ol, high relative abundances of cholesta-5,22E-dien-3β-ol are typical for Cymatosirales, high relative abundances of 24-ethylcholesta-5,22E-dien-3β-ol are characteristic for related Amphora, Amphiprora, and Entomoneis species, and a combination of high relative abundances of 24-methylcholest-5-en-3β-ol, 24-methylcholesta-5,24(28)-dien-3β-ol, and 24-ethylcholest-5-en-3β-ol is typical for Attheya species. High contributions of 24-methylcholesta-5,22E-dien-3β-ol (>50% of all sterols) seem to be restricted to pennate diatoms. None of the major sterols found in diatoms can be used as an unambiguous diatom biomarker because all of them have been reported as common sterols in other algal groups.
181 citations
TL;DR: The results showed that the total area of a PC/cholesterol bilayer is primarily determined by the molecular packing in the cholesterol sterol ring region, and an alternative analysis of area per molecule within this region is proposed, which takes into account the cholesterol tilt angle and the practical incompressibility ofolesterol sterol rings.
Abstract: The condensing effect of cholesterol in dioleoylphosphatidylcholine (DOPC) lipid bilayers was systematically investigated via atomistic molecular dynamics (MD) simulation. Fourteen independent 200 ns simulations, spanning the entire range of cholesterol mole fraction (x(c)) in DOPC bilayers (i.e., from x(c) = 0 to 0.66), were performed at 323 K. The molecular areas occupied by DOPC and cholesterol at different distances from the bilayer center were analyzed using a slicing method based on the VDW radii of atoms. Curiously, while the average area per lipid and the cholesterol tilt angle, with respect to the bilayer normal, both show monotonic decreases as x(c) increases, the average bilayer height shows a significant decrease for x(c) > 0.35, following an initial increase. The calculated partial-specific areas of lipids clearly show the condensing effect of cholesterol. The VDW areal analysis showed that the condensing effect is limited only to the cholesterol sterol ring region, where the acyl chains of DOPC are severely compressed by cholesterol. As x(c) increases, the headgroups of DOPC gradually expand along the bilayer-aqueous interface to occupy more lateral area. Thus, it confirmed a key prediction of the umbrella model. At high cholesterol mole fractions, the calculated area per DOPC and area per cholesterol using some existing methods showed an inconsistent result: both increase while the overall area per lipid decreases. The inconsistency stems from the problematic assumption that cholesterol and DOPC have cylindrical shape and the same height. Our results showed that the total area of a PC/cholesterol bilayer is primarily determined by the molecular packing in the cholesterol sterol ring region. An alternative analysis of area per molecule within this region is proposed, which takes into account the cholesterol tilt angle and the practical incompressibility of cholesterol sterol rings. The new calculation shows that the majority of the area lost due to the cholesterol condensing effect is taken from PC molecules.
166 citations
TL;DR: It is demonstrated that CYCLO administration acutely reverses the cholesterol transport defect seen in the NPC1 mouse at any age, and this reversal allows the sequestered sterol to be excreted from the body as bile acid.
161 citations
TL;DR: NPC1L1‐dependent sterol uptake seems to be a clathrin‐mediated endocytic process and is regulated by cellular cholesterol content, which has beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis.
TL;DR: The results suggest that missense mutations in ERG3 might arise in C. albicans more frequently than currently supposed and that the clinical significance of erg3 mutants, including those in which additional mechanisms also contribute to resistance, should not be discounted.
Abstract: Sterol analysis identified four Candida albicans erg3 mutants in which ergosta 7,22-dienol, indicative of perturbations in sterol Δ(5,6)-desaturase (Erg3p) activity, comprised >5% of the total sterol fraction. The erg3 mutants (CA12, CA488, CA490, and CA1008) were all resistant to fluconazole, voriconazole, itraconazole, ketoconazole, and clotrimazole under standard CLSI assay conditions (MIC values, ≥256, 16, 16, 8, and 1 μg ml⁻¹, respectively). Importantly, CA12 and CA1008 retained an azole-resistant phenotype even when assayed in the presence of FK506, a multidrug efflux inhibitor. Conversely, CA488, CA490, and three comparator isolates (CA6, CA14, and CA177, in which ergosterol comprised >80% of the total sterol fraction and ergosta 7,22-dienol was undetectable) all displayed azole-sensitive phenotypes under efflux-inhibited assay conditions. Owing to their ergosterol content, CA6, CA14, and CA177 were highly sensitive to amphotericin B (MIC values, <0.25 μg ml⁻¹); CA1008, in which ergosterol comprised <2% of the total sterol fraction, was less sensitive (MIC, 1 μg ml⁻¹). CA1008 harbored multiple amino acid substitutions in Erg3p but only a single conserved polymorphism (E266D) in sterol 14α-demethylase (Erg11p). CA12 harbored one substitution (W332R) in Erg3p and no residue changes in Erg11p. CA488 and CA490 were found to harbor multiple residue changes in both Erg3p and Erg11p. The results suggest that missense mutations in ERG3 might arise in C. albicans more frequently than currently supposed and that the clinical significance of erg3 mutants, including those in which additional mechanisms also contribute to resistance, should not be discounted.
TL;DR: A clinical isolate of Candida albicans was identified as an erg5 (encoding sterol C22 desaturase) mutant in which ergosterol was not detectable and ergosta 5,7-dienol comprised > 80% of the total sterol fraction as discussed by the authors.
Abstract: A clinical isolate of Candida albicans was identified as an erg5 (encoding sterol C22 desaturase) mutant in which ergosterol was not detectable and ergosta 5,7-dienol comprised >80% of the total sterol fraction. The mutant isolate (CA108) was resistant to fluconazole, voriconazole, itraconazole, ketoconazole, and clotrimazole (MIC values, 64, 8, 2, 1, and 2 μg ml−1, respectively); azole resistance could not be fully explained by the activity of multidrug resistance pumps. When susceptibility tests were performed in the presence of a multidrug efflux inhibitor (tacrolimus; FK506), CA108 remained resistant to azole concentrations higher than suggested clinical breakpoints for C. albicans (efflux-inhibited MIC values, 16 and 4 μg ml−1 for fluconazole and voriconazole, respectively). Gene sequencing revealed that CA108 was an erg11 erg5 double mutant harboring a single amino acid substitution (A114S) in sterol 14α-demethylase (Erg11p) and sequence repetition (10 duplicated amino acids), which nullified C22 desaturase (Erg5p) function. Owing to a lack of ergosterol, CA108 was also resistant to amphotericin B (MIC, 2 μg ml−1). This constitutes the first report of a C. albicans erg5 mutant isolated from the clinic.
TL;DR: Using the results of recently published experimental and computer-modeling studies to provide a new more dynamic molecular interpretation of sterol-lipid interactions, it is suggested that the established view of the rigid sterol ring system and extended alkyl side-chain obtained from physical studies of cholesterol-phospholipid mixtures may not apply in lipid mixtures differing in their sterol chemical structure.
TL;DR: What is known about these processes and the dynamics of cholesterol in the vertebrate retina are reviewed and some future avenues of research in this area are indicated.
TL;DR: The alteration to sterol profiles in cvp1 mutants affect auxin response, demonstrated by weak auxin insensitivity, enhanced axr1 auxin resistance, ectopically expressed DR5:β-glucuronidase in developing embryos, and defective response to auxin-inhibited PIN2-green fluorescent protein endocytosis.
Abstract: Plant sterols are structural components of cell membranes that provide rigidity, permeability, and regional identity to membranes. Sterols are also the precursors to the brassinosteroid signaling molecules. Evidence is accumulating that specific sterols have roles in pattern formation during development. COTYLEDON VASCULAR PATTERNING1 (CVP1) encodes C-24 STEROL METHYLTRANSFERASE2 (SMT2), one of three SMTs in Arabidopsis (Arabidopsis thaliana). SMT2 and SMT3, which also encodes a C-24 SMT, catalyze the reaction that distinguishes the synthesis of structural sterols from signaling brassinosteroid derivatives and are highly regulated. The deficiency of SMT2 in the cvp1 mutant results in moderate developmental defects, including aberrant cotyledon vein patterning, serrated floral organs, and reduced stature, but plants are viable, suggesting that SMT3 activity can substitute for the loss of SMT2. To test the distinct developmental roles of SMT2 and SMT3, we identified a transcript null smt3 mutant. Although smt3 single mutants appear wild type, cvp1 smt3 double mutants show enhanced defects relative to cvp1 mutants, such as discontinuous cotyledon vein pattern, and produce novel phenotypes, including defective root growth, loss of apical dominance, sterility, and homeotic floral transformations. These phenotypes are correlated with major alterations in the profiles of specific sterols but without significant alterations to brassinosteroid profiles. The alterations to sterol profiles in cvp1 mutants affect auxin response, demonstrated by weak auxin insensitivity, enhanced axr1 auxin resistance, ectopically expressed DR5:β-glucuronidase in developing embryos, and defective response to auxin-inhibited PIN2-green fluorescent protein endocytosis. We discuss the developmental roles of sterols implied by these results.
TL;DR: Analysis of leaf lipid composition during the Arabidopsis thaliana-Pseudomonas syringae interaction found that accumulation of the phytosterol stigmasterol is a significant plant metabolic process that occurs upon bacterial leaf infection.
Abstract: Upon inoculation with pathogenic microbes, plants induce an array of metabolic changes that potentially contribute to induced resistance or even enhance susceptibility. When analysing leaf lipid composition during the Arabidopsis thaliana-Pseudomonas syringae interaction, we found that accumulation of the phytosterol stigmasterol is a significant plant metabolic process that occurs upon bacterial leaf infection. Stigmasterol is synthesized from beta-sitosterol by the cytochrome P450 CYP710A1 via C22 desaturation. Arabidopsis cyp710A1 mutant lines impaired in pathogen-inducible expression of the C22 desaturase and concomitant stigmasterol accumulation are more resistant to both avirulent and virulent P. syringae strains than wild-type plants, and exogenous application of stigmasterol attenuates this resistance phenotype. These data indicate that induced sterol desaturation in wild-type plants favours pathogen multiplication and plant susceptibility. Stigmasterol formation is triggered through perception of pathogen-associated molecular patterns such as flagellin and lipopolysaccharides, and through production of reactive oxygen species, but does not depend on the salicylic acid, jasmonic acid or ethylene defence pathways. Isolated microsomal and plasma membrane preparations exhibited a similar increase in the stigmasterol/beta-sitosterol ratio as whole-leaf extracts after leaf inoculation with P. syringae, indicating that the stigmasterol produced is incorporated into plant membranes. The increased contents of stigmasterol in leaves after pathogen attack do not influence salicylic acid-mediated defence signalling but attenuate pathogen-induced expression of the defence regulator flavin-dependent monooxygenase 1. P. syringae thus promotes plant disease susceptibility through stimulation of sterol C22 desaturation in leaves, which increases the stigmasterol to beta-sitosterol ratio in plant membranes.
TL;DR: It is shown that Drosophila require both bulk membrane sterol and steroid hormones in order to complete adult development, and sterols are dispensable for maintaining the basic membrane biophysical properties required for cell viability.
Abstract: The high sterol concentration in eukaryotic cell membranes is thought to influence membrane properties such as permeability, fluidity and microdomain formation. Drosophila cannot synthesize sterols, but do require them for development. Does this simply reflect a requirement for sterols in steroid hormone biosynthesis, or is bulk membrane sterol also essential in Drosophila? If the latter is true, how do they survive fluctuations in sterol availability and maintain membrane homeostasis? Here, we show that Drosophila require both bulk membrane sterol and steroid hormones in order to complete adult development. When sterol availability is restricted, Drosophila larvae modulate their growth to maintain membrane sterol levels within tight limits. When dietary sterol drops below a minimal threshold, larvae arrest growth and development in a reversible manner. Strikingly, membrane sterol levels in arrested larvae are dramatically reduced (dropping sixfold on average) in most tissues except the nervous system. Thus, sterols are dispensable for maintaining the basic membrane biophysical properties required for cell viability; these functions can be performed by non-sterol lipids when sterols are unavailable. However, bulk membrane sterol is likely to have essential functions in specific tissues during development. In tissues in which sterol levels drop, the overall level of sphingolipids increases and the proportion of different sphingolipid variants is altered. These changes allow survival, but not growth, when membrane sterol levels are low. This relationship between sterols and sphingolipids could be an ancient and conserved principle of membrane homeostasis.
TL;DR: Fan et al. as mentioned in this paper analyzed the free sterol content of cerebrospinal fluid by a combination of charge tagging and liquid chromatography-tandem mass spectrometry, and the most abundant cholesterol metabolites were found to be C27 and C24 intermediates of the bile acid biosynthetic pathways with structures corresponding to 7α-hydroxy-3-oxocholest-4-en-26-oic acid (7.170 ± 2.826 ng/ml, mean ± S.D.
TL;DR: The effect of salt concentration on sterols yields has been studied varying the quantities of NaCl into culture medium, with good yields of total sterols achieved at lower salt concentration, while an increase in salt concentration resulted in a significant decrease in total sterol yield.
TL;DR: It is demonstrated that mass fecal sterol loss and macrophage RCT can proceed in the absence of biliary sterol secretion, challenging the obligate role of bile in RCT.
TL;DR: Results suggest that plasma PCSK9 levels may serve as a surrogate marker of hepatic SREBP-2 activity in humans, which is mirrored by measures of cholesterol synthesis in humans.
TL;DR: The Mycobacterium tuberculosis cytochrome P450 enzyme CYP142 is revealed as a cholesterol 27-oxidase with likely roles in host response modulation and cholesterol metabolism, and high affinity for azole antibiotics was demonstrated, highlighting their therapeutic potential.
TL;DR: A functional redundancy in the essential C26-monooxygenase activity of M. tuberculosis is established and two other cytochrome P450 enzymes, CYP125A1 and CYP142A1, are validated as possible drug targets.
TL;DR: In conclusion, inhibition of ERK1/2 and activation of LXR synergistically induced macrophage cholesterol efflux and ABCA1 expression suggests that ERK 1/2 activity can play an important role in macrophages cholesterol trafficking.
TL;DR: Recent evidence of sterol transfer activity by OSBP/ORPs suggests that other seemingly disparate functions could be the result of alterations in membrane sterol distribution or ancillary to this primary activity.
Abstract: Cholesterol and its numerous oxygenated derivatives (oxysterols) profoundly affect the biophysical properties of membranes, and positively and negatively regulate sterol homoeostasis through interaction with effector proteins. As the bulk of cellular sterols are segregated from the sensory machinery that controls homoeostatic responses, an important regulatory step involves sterol transport or signalling between membrane compartments. Evidence for rapid, energy-independent transport between organelles has implicated transport proteins, such as the eukaryotic family of OSBP (oxysterol-binding protein)/ORPs (OSBP-related proteins). Since the founding member of this family was identified more than 25 years ago, accumulated evidence has implicated OSBP/ORPs in sterol signalling and/or sterol transport functions. However, recent evidence of sterol transfer activity by OSBP/ORPs suggests that other seemingly disparate functions could be the result of alterations in membrane sterol distribution or ancillary to this primary activity.
TL;DR: Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetIMibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug Therapy.
Abstract: Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-bind-ing cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy.
TL;DR: The reduced intestinal fatty acid uptake observed with beta-glucan is associated with inhibition of genes regulating intestinal uptake and synthesis of lipids, and raises the possibility of their selective use to reduce their intestinal absorption.
Abstract: Background
Dietary fiber reduces the intestinal absorption of nutrients and the blood concentrations of cholesterol and triglycerides.
TL;DR: To elucidate the molecular nature of the AmB selectivity for ergosterol-containing membranes, computational methods are used to study the formation of the putative AmB/sterol complexes in a lipid bilayer and suggest a possible origin of the increased selectivity of a novel class of less toxic AmB derivatives.
Abstract: Amphotericin B (AmB) is a well-known polyene antibiotic used to treat systemic fungal infections. It is commonly accepted that the presence of sterols in the membrane is essential for the AmB biological activity, that is, for the formation of transmembrane ion channels. The selective toxicity of AmB for fungal cells is attributed to the fact that it is more potent against fungal cell membranes containing ergosterol than against the mammalian membranes with cholesterol. According to the "primary complex" hypothesis, AmB associates with sterols in a membrane to form binary complexes, which may subsequently assemble into a barrel-stave channel. To elucidate the molecular nature of the AmB selectivity for ergosterol-containing membranes, in the present work, we used computational methods to study the formation of the putative AmB/sterol complexes in a lipid bilayer. The free energy profiles for the AmB-sterol association in phospholipid bilayers containing 30 mol % of sterols were calculated and thoroughly analyzed. The results obtained confirm the formation of specific AmB/ergosterol complexes and are used to determine the energetic and structural origin of the enhanced affinity of AmB for ergosterol than for cholesterol. The significance of this affinity difference for the mechanism of action of AmB is discussed. The data obtained allowed us also to suggest a possible origin of the increased selectivity of a novel class of less toxic AmB derivatives.
TL;DR: A number of different food components are known to reduce plasma and LDL-cholesterol levels by affecting intestinal cholesterol absorption, including soluble fibers, phytosterols, saponins, phospholipids, soy protein and stearic acid.