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Search Results: 1 - 10 of 210102 matches for " Dieter Lütjohann "
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Sterol Lipid Metabolism in Down Syndrome Revisited: Down Syndrome Is Associated with a Selective Reduction in Serum Brassicasterol Levels
Gavin Tansley,Daniel T. Holmes,Dieter Lütjohann,Elizabeth Head,Cheryl L. Wellington
Current Gerontology and Geriatrics Research , 2012, DOI: 10.1155/2012/179318
Abstract: Over the past 15 years, insights into sterol metabolism have improved our understanding of the relationship between lipids and common conditions such as atherosclerosis and Alzheimer’s Disease (AD). A better understanding of sterol lipid metabolism in individuals with Down Syndrome (DS) may help elucidate how this population’s unique metabolic characteristics influence their risks for atherosclerosis and AD. To revisit the question of whether sterol lipid parameters may be altered in DS subjects, we performed a pilot study to assess traditional serum sterol lipids and lipoproteins, as well as markers of sterol biosynthesis, metabolites, and plant sterols in 20 subjects with DS compared to age-matched controls. Here we report that the levels of nearly all lipids and lipoproteins examined are similar to control subjects, suggesting that trisomy 21 does not lead to pronounced general alterations in sterol lipid metabolism. However, the levels of serum brassicasterol were markedly reduced in DS subjects. 1. Introduction 1.1. Down Syndrome Down Syndrome (trisomy 21) is the most common chromosomal abnormality, occurring in approximately 1 in 800 live births. DS is characterized by typical dysmorphic features, congenital abnormalities, and other medical conditions. Over the past 15 years, the life expectancy of individuals with DS has increased significantly, with the median age of death currently approaching 50 years [1], an age where the incidence of many common diseases of aging is high. Importantly, there are several differences in the way individuals with DS appear to age compared to the general population. Chief among these is the inevitable appearance of Alzheimer’s Disease (AD) neuropathology by the age of 35 years [2]. Individuals with DS have also been reported to be relatively resistant to developing atherosclerosis despite the presence of an unfavorable plasma lipid profile [3]. AD and atherosclerosis are each complex, multifactorial diseases with both genetic and environmental contributors [4, 5]. As lipid metabolism contributes to the pathogenesis of both disorders [4, 5], studying lipid metabolic markers in the unique clinical situation of DS may allow our understanding of the pathogenesis and risk factors of these diseases to be refined for both the DS and the general populations. 1.2. Atherosclerosis in DS Since Murdoch described a complete lack of atheroma in five institutionalized people with DS, there has been considerable interest in DS as an “atheroma-free” model [6]. Two subsequent post-mortem studies also demonstrated lower atheroma
Beneficial Effects of Sitostanol on the Attenuated Immune Function in Asthma Patients: Results of an In Vitro Approach
Florence Brüll, Ronald P. Mensink, Mandy F. Steinbusch, Constanze Husche, Dieter Lütjohann, Geert-Jan Wesseling, Jogchum Plat
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046895
Abstract: Background In vitro and animal studies have suggested that plant sterols and stanols increase cytokine production by T-helper-1 cells. This may be beneficial for patient groups characterized by a T-helper-2 dominant immune response, e.g. asthma patients. (1) to evaluate whether sitostanol induces a T-helper-1 shift in peripheral blood mononuclear cells (PBMCs) from asthma patients, and (2) to unravel the role of regulatory T-cells in this respect. Methodology/Principal Findings PBMCs from 10 asthma patients and 10 healthy subjects were isolated and incubated with 1.2 μM sitostanol, while stimulated with 5 μg/ml PHA. Similar amounts of cholesterol were used to determine whether effects were specific for plant stanols or for sterols in general. Changes in cytokine production were measured using antibody arrays and ELISAs. Changes in regulatory T-cell population size were measured by flow cytometry, using intracellular Foxp3 staining. Sitostanol increased production of IFNγ by 6.5% and IL-2 by 6.0% compared to cholesterol (p<0.01). No changes in IL-4 and IL-13 were found. Interestingly, this effect was only present in PBMCs from asthma patients. The number of Foxp3+ cells tended to increase and their activity, measured by IL-10 production, increased after sitostanol treatment in PBMCs from asthma patients compared to controls by 32.3% (p = 0.077) and 13.3% (p<0.05), respectively. Conclusions/Significance Altogether, the sitostanol-induced Thelper-1 shift in PBMCs from asthma patients and the stimulating effects of sitostanol on Treg cell numbers and activity indicate a possible novel approach for plant stanol ester enriched functional foods in the amelioration of asthmatic symptoms. Functional effects, however, require further evaluation.
AT1-receptor-deficiency induced atheroprotection in diabetic mice is partially mediated via PPARgamma
Vedat Tiyerili, Ulrich M Becher, Adem Aksoy, Dieter Lütjohann, Sven Wassmann, Georg Nickenig, Cornelius FH Mueller
Cardiovascular Diabetology , 2013, DOI: 10.1186/1475-2840-12-30
Abstract: Methods and results: ApoE-/- and ApoE-/-/AT1R-/--mice were rendered diabetic by intraperitoneal injections of streptozotocin. Diabetic and non-diabetic ApoE-/--mice were further randomized to receive the AT1R antagonist telmisartan, the selective PPARgamma antagonist GW9662, telmisartan and GW9662 or vehicle for 18 weeks. Diabetic and non-diabetic ApoE-/-/AT1R-/--mice were randomized to receive either GW9662 or vehicle. GW9662 treatment in diabetic ApoE-/- and diabetic ApoE-/-/AT1-/--mice resulted in the highest elevation of fasting blood glucose levels, whereas telmisartan treatment and AT1 deficiency in ApoE-/--mice showed the lowest fasting blood glucose levels. Diabetic ApoE-/--mice displayed severe impairment of endothelial function, enhanced oxidative stress and increased atherosclerotic lesion formation. ApoE-/-/AT1R-/- and telmisartan-treated ApoE-/--mice showed a significantly better endothelial function, decreased oxidative stress and reduced atherosclerotic lesion formation. Treatment of diabetic ApoE-/- and ApoE-/-/AT1R-/--mice with the selective PPARgamma antagonist GW9662 omitted the atheroprotective effects of AT1R deficiency or AT1 antagonism.Genetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE-/--mice via the PPARgamma pathway.
Monocytes of patients with familial hypercholesterolemia show alterations in cholesterol metabolism
Sandy Mosig, Knut Rennert, Petra Büttner, Siegfried Krause, Dieter Lütjohann, Muhidien Soufi, Regine Heller, Harald Funke
BMC Medical Genomics , 2008, DOI: 10.1186/1755-8794-1-60
Abstract: Cholesterol and oxidized cholesterol metabolite serum levels of FH and of healthy, gender/age matched control subjects were measured by combined gas chromatography – mass spectroscopy. Monocytes from patients with FH and from healthy subjects were isolated by antibody-assisted density centrifugation. Gene expression profiles of isolated monocytes were measured using Affymetrix HG-U 133 Plus 2.0 microarrays. We compared monocyte gene expression profiles from FH patients with healthy controls using a Welch T-test with correction for multiple testing (p < 0.05; Benjamini Hochberg correction, False Discovery Rate = 0.05). The differential expression of FH associated genes was validated at the mRNA level by qRT-PCR and/or at the protein level by Western Blot or flow cytometry. Functional validation of monocyte scavenger receptor activities were done by binding assays and dose/time dependent uptake analysis using native and oxidized LDL.Using microarray analysis we found in FH patients a significant up-regulation of 1,617 genes and a down-regulation of 701 genes compared to monocytes from healthy individuals. These include genes of proteins that are involved in the uptake, biosynthesis, disposition, and cellular efflux of cholesterol. In addition, plasma from FH patients contains elevated amounts of sterols and oxysterols. An increased uptake of oxidized as well as of native LDL by FH monocytes combined with a down-regulation of NPC1 and ABCA1 explains the lipid accumulation observed in these cells.Our data demonstrate that circulating FH monocytes show differences in cell physiology that may contribute to the early onset of atherosclerosis in this disease.Atherosclerosis is the primary cause of coronary heart disease (CHD) and stroke in Western societies [1]. It is characterized by the development of lipid-rich lesions in the arterial wall, in which foam cells, monocyte-derived lipid-laden macrophages, are frequently found.An important regulator of cellular cholesterol c
Fecal bile acid excretion and messenger RNA expression levels of ileal transporters in high risk gallstone patients
Jorge Herrera, Ludwig Amigo, Constanze Husche, Carlos Benítez, Silvana Zanlungo, Dieter Lütjohann, Juan Miquel, Flavio Nervi
Lipids in Health and Disease , 2009, DOI: 10.1186/1476-511x-8-53
Abstract: Excretion of fecal BA was measured in seven GS females and in ten GS-free individuals, all with a body mass index < 29. Participants ingested the stool marker Cr2O3 (300 mg/day) for 10 days, and fecal specimens were collected on the last 3 days. Chromium was measured by a colorimetric method, and BA was quantitated by gas chromatography/mass spectroscopy. Intake of calories, nutrients, fiber and cholesterol were similar in the GS and GS-free subjects. Mean BA excretion levels were 520 ± 80 mg/day for the GS-free group, and 461 ± 105 mg/day for the GS group. Messenger RNA expression levels were determined by RT-PCR on biopsy samples obtained from ileum during diagnostic colonoscopy (14 GS-free controls and 16 GS patients) and from liver during surgery performed at 8 and 10 AM (12 GS and 10 GS-free patients operated on for gastrointestinal malignancies), all with a body mass index < 29. Messenger RNA level of the BA transporter genes for ileal lipid binding protein, multidrug resistance-associated protein 3, organic solute transporter alpha, and organic solute transporter beta were similar in GS and GS-free subjects. Messenger RNA level of Cyp27A1, encoding the enzyme 27α-hydroxylase, the short heterodimer partner and farnesoid X receptor remained unchanged, whereas the mRNA level of Cyp7A1, the rate limiting step of BA synthesis, was increased more than 400% (p < 0.01) in the liver of GS compared to GS-free subjects.Hispanics with GS have fecal BA excretion rates and mRNA levels of genes for ileal BA transporters that are similar to GS-free subjects. However, mRNA expression levels of Cyp7A1 are increased in GS, indicating that regulation of BA synthesis is abnormal in Hispanics with GS.Cholesterol gallstone disease (GS) is prevalent worldwide, and is endemic among American Indians and Hispanics [1,2]. In GS, the primary abnormality is secretion by the liver into the gallbladder of bile that is supersaturated with cholesterol. This leads to precipitation of cholester
Cholesterol Synthesis Is Associated with Hepatic Lipid Content and Dependent on Fructose/Glucose Intake in Healthy Humans
Guenther Silbernagel,Dieter Lütjohann,Juergen Machann,Sabrina Meichsner,Konstantinos Kantartzis,Fritz Schick,Hans-Ulrich H ring,Norbert Stefan,Andreas Fritsche
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/361863
Abstract: Visceral obesity and fatty liver have been related to high synthesis and low absorption of cholesterol. This study aimed to investigate the associations of cholesterol metabolism with liver and visceral fat content in healthy humans. Another objective was to explore the effects of very-high-fructose and very-high-glucose diets on cholesterol homeostasis. We report on a cohort of 20 people (12 males, 8 females; age 30.5±2.0 years; body mass index 25.9±0.5 kg/m2) who completed a four-week dietary intervention study. Between the baseline and the followup examination the study participants in addition to a balanced weight-maintaining diet received 150 g of either fructose or glucose per day. Visceral and liver fat were measured with magnetic resonance (MR) imaging and 1H-MR spectroscopy, respectively. Cholesterol absorption and synthesis were estimated from the serum noncholesterol sterol concentrations. Performing cross-sectional analyses the lanosterol and desmosterol to cholesterol ratios were positively correlated with visceral and liver fat content (all <.03). The lathosterol to cholesterol ratio decreased in response to high-fructose diet (=.006) but not in response to high-glucose diet. To conclude, visceral and liver fat content are associated with cholesterol synthesis in healthy humans. Furthermore, cholesterol synthesis appears to be dependent on fructose/glucose intake.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gene Is a Risk Factor of Large-Vessel Atherosclerosis Stroke
Shérine Abboud, Pekka J. Karhunen, Dieter Lütjohann, Sirkka Goebeler, Teemu Luoto, Silvia Friedrichs, Terho Lehtimaki, Massimo Pandolfo, Reijo Laaksonen
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001043
Abstract: Background/Purpose Genetic variation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has been recently identified as an important determinant of plasma LDL-cholesterol and severity of coronary heart disease. We studied whether the PCSK9 gene is linked to the risk of ischemic stroke (IS) and with the development of intracranial atherosclerosis. Methods/Results The pivotal E670G polymorphism, tagging an important haplotype of the PCSK9 gene, was genotyped in two independent studies. The Belgium Stroke Study included 237 middle aged (45–60) Belgian patients, with small-vessel occlusion (SVO) and large-vessel atherosclerosis stroke (LVA), and 326 gender and ethnicity matched controls (>60 yrs) without a history of stroke. In multivariate analysis the minor allele (G) carriers appeared as a significant predictor of LVA (OR = 3.52, 95% CI 1.25–9.85; p = 0.017). In a Finnish crossectional population based consecutive autopsy series of 604 males and females (mean age 62.5 years), G-allele carriers tended to have more severe allele copy number-dependent (p = 0.095) atherosclerosis in the circle of Willis and in its branches. Conclusion Our findings in this unique combination of clinical and autopsy data, provide evidence that PCSK9 gene associates with the risk of LVA stroke subtype, and suggest that the risk is mediated by the severity of intracranial atherosclerosis.
A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-Induced Changes in Muscle
Reijo Laaksonen, Mikko Katajamaa, Hannu P?iv?, Marko Sysi-Aho, Lilli Saarinen, P?ivi Junni, Dieter Lütjohann, Joél Smet, Rudy Van Coster, Tuulikki Sepp?nen-Laakso, Terho Lehtim?ki, Juhani Soini, Matej Ore?i?
PLOS ONE , 2006, DOI: 10.1371/journal.pone.0000097
Abstract: Background Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. Methodology We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo. Principal Findings High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. Conclusions High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.
Internalization of Modified Lipids by CD36 and SR-A Leads to Hepatic Inflammation and Lysosomal Cholesterol Storage in Kupffer Cells
Veerle Bieghs, Fons Verheyen, Patrick J. van Gorp, Tim Hendrikx, Kristiaan Wouters, Dieter Lütjohann, Marion J. J. Gijbels, Maria Febbraio, Christoph J. Binder, Marten H. Hofker, Ronit Shiri-Sverdlov
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034378
Abstract: Background & Aims Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs). Methods & Results Ldlr?/? mice were transplanted with wild-type (Wt), Cd36?/? or Msr1?/? bone marrow and fed a Western diet for 3months. Cd36?/?- and Msr1?/?- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36?/?- and Msr1?/?-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation. Conclusion CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH.
The Relationships of Markers of Cholesterol Homeostasis with Carotid Intima-Media Thickness
Oliver Weing?rtner,Tobias Pinsdorf,Kyrill S. Rogacev,Lutz Bl?mer,Yvonne Grenner,Stefan Gr?ber,Christof Ulrich,Matthias Girndt,Michael B?hm,Danilo Fliser,Ulrich Laufs,Dieter Lütjohann,Gunnar H. Heine
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013467
Abstract: The relationship of cholesterol homeostasis and carotid intima-media thickness (cIMT) is unknown. To address this, we assessed markers of cholesterol homeostasis (serum plant sterols and cholesterol precursor concentrations as surrogate measures of cholesterol absorption and synthesis, respectively) and cIMT in a middle-aged, statin-naive population.
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