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Tamara Gojkovic, Sandra Vladimirov, Vesna Spasojevic-Kalimanovska, Aleksandra Zeljkovic, Jelena Vekic, Dimitra Kalimanovska-Ostric, Ivana Djuricic, Sladjana Sobajic, Zorana Jelic-Ivanovic
BACKGROUND: Cholesterol homeostasis disorders may cause dyslipidemia, atherosclerosis progression and coronary artery disease (CAD) development. Evaluation of non-cholesterol sterols (NCSs) as synthesis and absorption markers, and lipoprotein particles quality may indicate the dyslipidemia early development. This study investigates associations of different cholesterol homeostasis patterns with low-density (LDL) and high-density lipoproteins (HDL) subclasses distribution in statin-treated and statin-untreated CAD patients, and potential use of aforementioned markers for CAD treatment optimization...
October 8, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
Matthew Peach, Ren Xu, Dan Fitzpatrick, Lisa Hamilton, Ransi Somaratne, Rob Scott, Scott M Wasserman, C Stephen Djedjos
The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. PCSK9 inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-C, but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial...
October 5, 2016: Journal of Lipid Research
Inci Kazkayasi, Muhammad-Al-Mustafa Ismail, Cristina Parrado-Fernandez, Ingemar Björkhem, Can Pekiner, Serdar Uma, Angel Cedazo-Minguez, Nihan Burul-Bozkurt
Several studies demonstrated that Diabetes mellitus (DM) enhances the risk for Alzheimer's disease (AD). Although hyperglycemia and perturbed function of insulin signaling have been proposed to contribute to AD pathogenesis, the molecular mechanisms behind this association is not clear yet. Seladin-1 is an enzyme catalyzing the last step in cholesterol biosynthesis converting desmosterol to cholesterol. The neuroprotective function of seladin-1 has gained interest in AD research recently. Seladin-1 has anti-apoptotic properties and regulates the expression of β-secretase (BACE-1)...
September 14, 2016: Neuroscience Letters
Oliver Weingärtner, Ivan Bogeski, Carsten Kummerow, Stephan H Schirmer, Tim Vanmierlo, Gudrun Wagenpfeil, Markus Hoth, Michael Böhm, Dieter Lütjohann, Ulrich Laufs
This double-blind, randomized, placebo-controlled, cross-over intervention-study was conducted in healthy volunteers to evaluate the effects of plant sterol ester supplemented margarine on cholesterol, non-cholesterol sterols and oxidative stress in serum and monocytes. Sixteen volunteers, average age 34 years, with no or mild hypercholesterolemia were subjected to a 4 week period of daily intake of 3g plant sterols per day supplied via a supplemented margarine on top of regular eating habits. After a wash-out period of one week, volunteers switched groups...
July 26, 2016: Journal of Steroid Biochemistry and Molecular Biology
Christine Vianey-Saban, Cécile Acquaviva, David Cheillan, Sophie Collardeau-Frachon, Laurent Guibaud, Cécile Pagan, Magali Pettazzoni, Monique Piraud, Antonin Lamazière, Roseline Froissart
Inborn errors of metabolism (IEMs) that present with abnormal imaging findings in the second half of pregnancy are mainly lysosomal storage disorders (LSDs), cholesterol synthesis disorders (CSDs), glycogen storage disorder type IV (GSD IV), peroxisomal disorders, mitochondrial fatty acid oxidation defects (FAODs), organic acidurias, aminoacidopathies, congenital disorders of glycosylation (CDGs), and transaldolase deficiency. Their biological investigation requires fetal material. The supernatant of amniotic fluid (AF) is useful for the analysis of mucopolysaccharides, oligosaccharides, sialic acid, lysosphingolipids and some enzyme activities for LSDs, 7- and 8-dehydrocholesterol, desmosterol and lathosterol for CSDs, acylcarnitines for FAODs, organic acids for organic acidurias, and polyols for transaldolase deficiency...
September 2016: Journal of Inherited Metabolic Disease
R O Pinho, D M A Lima, H H Shiomi, J B Siqueira, C O Silveira, V R Faria, P S Lopes, S E F Guimarães, J D Guimarães
The objective of this study was to investigate the effect of cyclodextrin-loaded cholesterol conjugates addition to freezing extenders on plasma membrane viability of frozen-thawed spermatozoa of the Piau swine breed. Twenty semen samples were used from five males. The freezing extender was based on lactose-egg yolk extender, added to 2% glycerol, 3% dimethylacetamide. The addition of cyclodextrin-loaded cholesterol conjugates was performed after centrifugation, when semen was diluted with the cooling extender...
August 2016: Cryobiology
Valerie A Villareal, Dan Fu, Deirdre A Costello, Xiaoliang Sunney Xie, Priscilla L Yang
Hepatitis C virus (HCV) increases intracellular desmosterol without affecting the steady-state abundance of other sterols, and the antiviral activity of inhibitors of desmosterol synthesis is suppressed by the addition of exogenous desmosterol. These observations suggest a model in which desmosterol has a specific function, direct or indirect, in HCV replication and that HCV alters desmosterol homeostasis to promote viral replication. Here, we use stimulated Raman scattering (SRS) microscopy in combination with isotopically labeled sterols to show that HCV causes desmosterol to accumulate in lipid droplets that are closely associated with the viral NS5A protein and that are visually distinct from the broad distribution of desmosterol in mock-infected cells and the more heterogeneous and disperse lipid droplets to which cholesterol traffics...
July 15, 2016: ACS Chemical Biology
Hye-Young H Kim, Zeljka Korade, Keri A Tallman, Wei Liu, C David Weaver, Karoly Mirnics, Ned A Porter
A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels...
May 16, 2016: Chemical Research in Toxicology
Valerio Leoni, Thomas Nury, Anne Vejux, Amira Zarrouk, Claudio Caccia, Meryam Debbabi, Agnès Fromont, Randa Sghaier, Thibault Moreau, Gérard Lizard
In multiple sclerosis (MS) a process of white matter degradation leading to demyelination is observed. Oxidative stress, inflammation, apoptosis, necrosis and/or autophagy result together into a progressive loss of oligodendrocytes. 7-ketocholesterol (7KC), found increased in the cerebrospinal fluid of MS patients, triggers a rupture of RedOx homeostasis associated with mitochondrial dysfunctions, aptoptosis and autophagy (oxiapoptophagy) in cultured murine oligodendrocytes (158N). α-tocopherol is able to mild the alterations induced by 7KC partially restoring the cellular homeostasis...
March 25, 2016: Journal of Steroid Biochemistry and Molecular Biology
Qian Zhao, Chao Qian, Xin-Zhi Chen
A new highly stereoselective construction of the side chain of the C-24 and C-25 oxysterols has been achieved by using desmosterol acetate as the starting material and an improved Sharpless catalytic asymmetric dihydroxylation with 100% d.e. (diastereomeric excess) as the key step. The result is much better than the usual asymmetric dihydroxylation procedure. t-Butyl nitrite/2,2,6,6-tetramethylpiperidine N-oxyl radical/FeCl3 catalyst system was developed to activate molecular oxygen for the aerobic oxidation of 24-hydroxycholesterol and the 24-ketocholesterol was obtained in 86...
May 2016: Steroids
Lydie Boussicault, Sandro Alves, Antonin Lamazière, Anabelle Planques, Nicolas Heck, Lara Moumné, Gaëtan Despres, Susanne Bolte, Amélie Hu, Christiane Pagès, Laurie Galvan, Francoise Piguet, Patrick Aubourg, Nathalie Cartier, Jocelyne Caboche, Sandrine Betuing
Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC)...
March 2016: Brain: a Journal of Neurology
Xiaoping Quan, Xiuqiang Chen, Deliang Sun, Bo Xu, Linlin Zhao, Xiaoqian Shi, Hongsheng Liu, Bing Gao, Xiuli Lu
DHCR24 encodes 3β-hydroxysterol-Δ(24)-reductase (DHCR24) catalyzing the cholesterol synthesis from desmosterol using the flavin adenine dinucleotide (FAD) as a co-factor. It is generally accepted that U18666a inhibits the reductase activity of DHCR24, but the detailed mechanism remains elusive. To explore the mechanism of the inhibitory effect of U18666a on DHCR24, we performed molecular dynamics (MD) simulations of two complexes including complexes of DHCR24-FAD-desmosterol enzymatic reactive components with and without the inhibitor U18666a...
February 2016: Journal of Molecular Modeling
Lucía Baila-Rueda, María Rosario Pérez-Ruiz, Estíbaliz Jarauta, María Teresa Tejedor, Rocío Mateo-Gallego, Iztiar Lamiquiz-Moneo, Isabel de Castro-Orós, Ana Cenarro, Fernando Civeira
BACKGROUND AND AIM: The genetic cause and pathogenic mechanism of approximately 20-40% of autosomal dominant hypercholesterolemias (ADH) are unknown. Increased cholesterol intestinal absorption has been associated to ADH. If this variation contributes to their pathogenesis is unknown. METHODS AND RESULTS: We studied cholesterol absorption (phytosterols and cholestanol serum concentrations) and cholesterol synthesis (desmosterol serum concentration) in 20 families with ADH without causal mutations in LDLR, APOB, PCSK9 or APOE genes (non-FH ADH) selected from 54 non-FH ADH probands with (non-cholesterol sterol concentrations above 75th percentile) and without (under 75th percentile) hyperabsorption...
March 2016: Atherosclerosis
Zeljka Korade, Hye-Young H Kim, Keri A Tallman, Wei Liu, Katalin Koczok, Istvan Balogh, Libin Xu, Karoly Mirnics, Ned A Porter
Well-established cell culture models were combined with new analytical methods to assess the effects of small molecules on the cholesterol biosynthesis pathway. The analytical protocol, which is based on sterol derivation with the dienolphile PTAD, was found to be reliable for the analysis of 7-DHC and desmosterol. The PTAD method was applied to the screening of a small library of pharmacologically active substances, and the effect of compounds on the cholesterol pathway was determined. Of some 727 compounds, over 30 compounds decreased 7-DHC in Dhcr7-deficient Neuro2a cells...
February 11, 2016: Journal of Medicinal Chemistry
Julia Kühn, Frank Hirche, Stefanie Geissler, Gabriele I Stangl
INTRODUCTION: Due to the high prevalence of vitamin D deficiency, strategies are needed to improve vitamin D status. Food components can affect vitamin D metabolism and have to be considered when estimating the efficacy of vitamin D supplements. 7-dehydrocholesterol (7-DHC) occurs naturally in food, but its impact on vitamin D metabolism has not yet been examined. METHODS: Three groups of male C57BL/6 mice (n=12 per group) were placed on a diet that contained 0, 2...
December 17, 2015: Journal of Steroid Biochemistry and Molecular Biology
Thomas D Dayspring, Stephen A Varvel, Leila Ghaedi, Dawn L Thiselton, James Bruton, Joseph P McConnell
BACKGROUND: Circulating noncholesterol sterols/stanols (NCS) are used in clinical lipidology as surrogate measures of cholesterol synthesis and absorption, where they can be valuable tools in assessing cholesterol metabolism and personalizing therapies in patients with dyslipidemia. OBJECTIVES: To describe the distributions of plasma NCS concentrations and inter-NCS correlations in a large cohort of American patients constituting a clinical laboratory database, and to investigate the relationship between circulating NCS, age, sex, and apolipoprotein E (APOE) genotype...
November 2015: Journal of Clinical Lipidology
Fabian Kreilaus, Adena S Spiro, Anthony J Hannan, Brett Garner, Andrew M Jenner
BACKGROUND: Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. OBJECTIVE: This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease...
2015: Journal of Huntington's Disease
Fabian Kreilaus, Adena S Spiro, Catriona A McLean, Brett Garner, Andrew M Jenner
AIMS: Cholesterol plays an essential role in membrane structure and function, being especially important in the brain. Alteration of brain cholesterol synthesis and metabolism has been demonstrated in several Huntington's disease (HD) mouse and cell models; however, less is known about these alterations in human tissue. This study aimed to identify alterations to cholesterol synthetic and metabolic pathways in human HD brain tissue. METHODS: A broad range of cholesterol synthetic precursors, metabolites and oxidation products were measured by gas chromatography-tandem mass spectrometry in five regions of human post mortem HD brain and compared with age- and sex-matched control tissues...
October 2016: Neuropathology and Applied Neurobiology
Matthew G K Benesch, Ruthven N A H Lewis, Ronald N McElhaney
We performed differential scanning calorimetric (DSC) and Fourier transform infrared (FTIR) spectroscopic studies of the effects of cholesterol (CHOL), 7-dehydrocholeterol (7DHC) and desmosterol (DES) on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine (DPPC) bilayer membranes. 7DHC and DES are the immediate biosynthetic precursors of CHOL in the Kandutch-Russell and Bloch pathways and 7DHC and DES differ in structure from CHOL only by the presence of an additional double bond at C7 of ring B or C24 of the alkyl side chain, respectively...
October 2015: Chemistry and Physics of Lipids
Zobair M Younossi, Maria Stepanova, Michael Estep, Francesco Negro, Paul J Clark, Sharon Hunt, Qinghua Song, Matthew Paulson, Luisa M Stamm, Diana M Brainard, G Mani Subramanian, John G McHutchison, Keyur Patel
BACKGROUND & AIMS: Hepatitis C virus (HCV) modulates host lipid metabolism for its replication and lifecycle. Our aims were to assess changes in the serum lipid and distal (post-squalene) cholesterol biosynthesis metabolite profile of HCV genotypes (GT) 2 and 3 patients treated with sofosbuvir+ribavirin. METHODS: Serum samples [baseline, treatment week 12, 4weeks post-treatment] were analyzed for apolipoproteins B and E (apoB/E), total cholesterol, HDL, LDL, and 11 post-squalene sterol metabolites using a GC/MS platform...
January 2016: Journal of Hepatology
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