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Peter J Meikle, Scott A Summers
Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear...
October 21, 2016: Nature Reviews. Endocrinology
Alba Di Pardo, Enrico Amico, Vittorio Maglione
Huntington Disease (HD) is a genetic neurodegenerative disorder characterized by broad types of cellular and molecular dysfunctions that may affect both neuronal and non-neuronal cell populations. Among all the molecular mechanisms underlying the complex pathogenesis of the disease, alteration of sphingolipids has been identified as one of the most important determinants in the last years. In the present study, besides the purpose of further confirming the evidence of perturbed metabolism of gangliosides GM1, GD1a, and GT1b the most abundant cerebral glycosphingolipids, in the striatal and cortical tissues of HD transgenic mice, we aimed to test the hypothesis that abnormal levels of these lipids may be found also in the corpus callosum white matter, a ganglioside-enriched brain region described being dysfunctional early in the disease...
2016: Frontiers in Neuroscience
Isabel M López-Lara, Otto Geiger
The glycerophospholipids phosphatidylethanolamine, phosphatidylglycerol (PG), and cardiolipin (CL) are major structural components of bacterial membranes. In some bacteria, phosphatidylcholine or phosphatidylinositol and its derivatives form part of the membrane. PG or CL can be modified with the amino acid residues lysine, alanine, or arginine. Diacylglycerol is the lipid anchor from which syntheses of phosphorus-free glycerolipids, such as glycolipids, sulfolipids, or homoserine-derived lipids initiate. Many membrane lipids are subject to turnover and some of them are recycled...
October 17, 2016: Biochimica et Biophysica Acta
Zahir H Alshehry, Piyushkumar A Mundra, Christopher K Barlow, Natalie A Mellett, Gerard Wong, Malcolm J McConville, John Simes, Andrew M Tonkin, David R Sullivan, Elizabeth H Barnes, Paul J Nestel, Bronwyn A Kingwell, Michel Marre, Bruce Neal, Neil R Poulter, Anthony Rodgers, Bryan Williams, Sophia Zoungas, Graham S Hillis, John Chalmers, Mark Woodward, Peter J Meikle
BACKGROUND: -Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. METHODS: -Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionisation-tandem mass spectrometry on a case-cohort (n=3,779) subset from the ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) trial...
October 18, 2016: Circulation
Junhui Shen, Jianfeng He, Fang Wang
In the past decades, much investigation has been done on the role of lipids in the development and progression of age-related macular degeneration (AMD). The lipids involved in those research studies had included PUFAs, phospholipids, sphingolipids, cholesterol, lipid protein, etc. There are a large number of clinical research studies on the association of PUFAs with the development and progression of AMD. The relationship between cholesterol level and AMD has been explored for decades and much data and analysis results have been obtained...
September 2016: Discovery Medicine
Susanne Grond, Thomas O Eichmann, Sandrine Dubrac, Dagmar Kolb, Matthias Schmuth, Judith Fischer, Debra Crumrine, Peter M Elias, Guenter Haemmerle, Rudolf Zechner, Achim Lass, Franz P W Radner
Mutations in PNPLA1 (Patatin-like phospholipase domain-containing 1) have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the generation of omega-O-acylceramides and led to an accumulation of non-esterified omega-hydroxy-ceramides...
October 14, 2016: Journal of Investigative Dermatology
Najaf Amin, Nadezhda M Belonogova, Olivera Jovanova, Rutger W W Brouwer, Jeroen G J van Rooij, Mirjam C G N van den Hout, Gulnara R Svishcheva, Robert Kraaij, Irina V Zorkoltseva, Anatoly V Kirichenko, Albert Hofman, André G Uitterlinden, Wilfred F J van IJcken, Henning Tiemeier, Tatiana I Axenovich, Cornelia M van Duijn
BACKGROUND: Despite high heritability, little success was achieved in mapping genetic determinants of depression-related traits by means of genome-wide association studies. METHODS: To identify genes associated with depressive symptomology, we performed a gene-based association analysis of nonsynonymous variation captured using exome-sequencing and exome-chip genotyping in a genetically isolated population from the Netherlands (n = 1999). Finally, we reproduced our significant findings in an independent population-based cohort (n = 1604)...
August 11, 2016: Biological Psychiatry
Katrin Anne Becker, Nadine Beckmann, Constantin Adams, Gabriele Hessler, Melanie Kramer, Erich Gulbins, Alexander Carpinteiro
Metastatic dissemination of cancer cells is one of the hallmarks of malignancy and accounts for approximately 90 % of human cancer deaths. Within the blood vasculature, tumor cells may aggregate with platelets to form clots, adhere to and spread onto endothelial cells, and finally extravasate to form metastatic colonies. We have previously shown that sphingolipids play a central role in the interaction of tumor cells with platelets; this interaction is a prerequisite for hematogenous tumor metastasis in at least some tumor models...
October 15, 2016: Clinical & Experimental Metastasis
Ismael González-García, Johan Fernø, Carlos Diéguez, Rubén Nogueiras, Miguel López
Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase (FAS) and AMP-activated protein kinase (AMPK), impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues non suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases, such as insulin resistance, cardiomyopathy, atherosclerosis and steatohepatitis...
October 11, 2016: Neuroendocrinology
Vi T Dang, Aric Huang, Lexy H Zhong, Yuanyuan Shi, Geoff H Werstuck
Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models...
October 10, 2016: Scientific Reports
Sara Tulipani, Magali Palau-Rodriguez, Antonio Miñarro Alonso, Fernando Cardona, Anna Marco-Ramell, Bozo Zonja, Miren Lopez de Alda, Araceli Muñoz-Garach, Alejandro Sanchez-Pla, Francisco J Tinahones, Cristina Andres-Lacueva
Metabolomic studies aimed to dissect the connection between the development of type 2 diabetes and obesity are still scarce. In the present study, fasting serum from sixty-four adult individuals classified into four sex-matched groups by their BMI [non-obese versus morbid obese] and the increased risk of developing diabetes [prediabetic insulin resistant state versus non-prediabetic non-insulin resistant] was analyzed by LC- and FIA-ESI-MS/MS-driven metabolomic approaches. Altered levels of [lyso]glycerophospholipids was the most specific metabolic trait associated to morbid obesity, particularly lysophosphatidylcholines acylated with margaric, oleic and linoleic acids [lysoPC C17:0: R=-0...
October 5, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
David L Ebenezer, Panfeng Fu, Vidyani Suryadevara, Yutong Zhao, Viswanathan Natarajan
Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes...
September 29, 2016: Advances in Biological Regulation
L Kuchař, B Asfaw, J Rybová, J Ledvinová
In recent years, mass spectrometry (MS) has become the dominant technology in lipidomic analysis. It is widely used in diagnosis and research of lipid metabolism disorders including those characterized by impairment of lysosomal functions and storage of nondegraded-degraded substrates. These rare diseases, which include sphingolipidoses, have severe and often fatal clinical consequences. Modern MS methods have contributed significantly to achieve a definitive diagnosis, which is essential in clinical practice to begin properly targeted patient care...
2016: Advances in Clinical Chemistry
Florian Fröhlich, Daniel K Olson, Romain Christiano, Robert V Farese, Tobias C Walther
Sphingolipids are essential components of eukaryotic cells with important functions in membrane biology and cellular signaling. Their levels are tightly controlled and coordinated with the abundance of other membrane lipids. How sphingolipid homeostasis is achieved is not yet well understood. Studies performed primarily in yeast showed that the phosphorylation states of several enzymes and regulators of sphingolipid synthesis are important, although a global understanding for such regulation is lacking. Here, we used high-resolution mass-spectrometry-based proteomics and phosphoproteomics to analyze the cellular response to sphingolipid synthesis inhibition...
September 26, 2016: Proteomics
Limin Hao, Oshrit Ben-David, Suzann M Babb, Anthony H Futerman, Bruce M Cohen, Edgar A Buttner
Defining the mechanisms of action of the anti-psychotic drug (APD), clozapine is of great importance, as clozapine is more effective and has therapeutic benefits in a broader range of psychiatric disorders than other APDs. Its range of actions have not been fully characterized. Exposure to APDs early in development causes dose-dependent developmental delay and lethality in C. elegans. A previous genome-wide RNAi screen for suppressors of clozapine-induced developmental delay and lethality revealed 40 candidate genes, including sms-1, which encodes a sphingomyelin synthase...
October 6, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Ewa Harasim-Symbor, Karolina Konstantynowicz-Nowicka, Adrian Chabowski
Synthetic and natural glucocorticoids are able to highly modify liver lipid metabolism, which is possibly associated with Nonalcoholic Fatty Liver Disease development. We have assessed changes in lipid and sphingolipid contents in hepatocytes, lipid composition and saturation status as well as the expression of proteins involved in fatty acid transport after both dexamethasone and palmitate treatments. The experiments were conducted on primary rat hepatocytes, incubated with either dexamethasone and/or palmitic acid during short (16h) and prolonged (40h) exposure...
October 5, 2016: Journal of Molecular Endocrinology
Hao Huang, Tian-Tian Tong, Lee-Fong Yau, Cheng-Yu Chen, Jia-Ning Mi, Jing-Rong Wang, Zhi-Hong Jiang
Drug resistance elicited by cancer cells continue to cause huge problems world-wide, for example, tens of thousands of patients are suffering from taxol-resistant human ovarian cancer. However, its biochemical mechanisms remain unclear. Sphingolipid metabolic dysregulation has been increasingly regarded as one of the drug-resistant mechanisms for various cancers, which in turn provides potential targets for overcoming the resistance. In the current study, a well-established LC-MS based sphingolipidomic approach was applied to investigate the sphingolipid metabolism of A2780 and taxol-resistant A2780 (A2780T) human ovarian cancer cell lines...
October 5, 2016: Scientific Reports
Min Park, Vincent Kaddai, Jianhong Ching, Kevin T Fridianto, Ryan J Sieli, Shigeki Sugii, Scott A Summers
The accumulation of sphingolipids in obesity leads to impairments in insulin sensitivity and mitochondrial metabolism, but the precise species driving these defects is unclear. We have modelled these obesity-induced effects in cultured C2C12 myotubes, using BSA-conjugated palmitate to increase synthesis of endogenous sphingolipids and inhibit insulin signaling and oxidative phosphorylation. Palmitate (a) induced the accumulation of SM precursors such as sphinganine, dihydroceramide, and ceramide, (b) inhibited insulin-stimulation of a central modulator of anabolic metabolism, Akt/PKB, (c) inhibited insulin-stimulated glycogen synthesis, and (d) decreased oxygen consumption and ATP synthesis...
October 4, 2016: Journal of Biological Chemistry
Miguel A Martín-Acebes, Ángela Vázquez-Calvo, Juan-Carlos Saiz
Flaviviruses are emerging arthropod-borne pathogens that cause life-threatening diseases such as yellow fever, dengue, West Nile encephalitis, tick-borne encephalitis, Kyasanur Forest disease, tick-borne encephalitis, or Zika disease. This viral genus groups >50 viral species of small enveloped plus strand RNA virus that are phylogenetically closely related to hepatitis C virus. Importantly, the flavivirus life cycle is intimately associated to host cell lipids. Along this line, flaviviruses rearrange intracellular membranes from the endoplasmic-reticulum of the infected cells to develop adequate platforms for viral replication and particle biogenesis...
October 1, 2016: Progress in Lipid Research
A Łukomska, I Baranowska-Bosiacka, M Budkowska, A Pilutin, M Tarnowski, K Dec, B Dołęgowska, E Metryka, D Chlubek, I Gutowska
Sphingolipids are the main components of the lipid membrane. They also perform structural functions and participate in many signal transmission processes. One of the bioactive sphingolipids is sphingosine-1-phosphate (S1P), a ligand for five G protein-coupled receptors (S1PRs1-5), which can also act as an intracellular second messenger. S1P is responsible for the stimulation of progenitor cells in the brain, but it can also induce apoptosis of mature neurons. This study is aimed at assessing the effect of pre- and neonatal exposure to permissible Pb concentrations on S1P levels and S1PR1 (EDG1) expression in the prefrontal cortex, cerebellum, and hippocampus of rats...
January 2017: Chemosphere
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