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Martinez-Una M.,University of the Basque Country | Varela-Rey M.,CIBER ISCIII | Cano A.,OWL | Fernandez-Ares L.,University of the Basque Country | And 14 more authors.
Hepatology | Year: 2013

Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are the primary genes involved in hepatic S-adenosylmethionine (SAMe) synthesis and degradation, respectively. Mat1a ablation in mice induces a decrease in hepatic SAMe, activation of lipogenesis, inhibition of triglyceride (TG) release, and steatosis. Gnmt-deficient mice, despite showing a large increase in hepatic SAMe, also develop steatosis. We hypothesized that as an adaptive response to hepatic SAMe accumulation, phosphatidylcholine (PC) synthesis by way of the phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway is stimulated in Gnmt-/- mice. We also propose that the excess PC thus generated is catabolized, leading to TG synthesis and steatosis by way of diglyceride (DG) generation. We observed that Gnmt-/- mice present with normal hepatic lipogenesis and increased TG release. We also observed that the flux from PE to PC is stimulated in the liver of Gnmt-/- mice and that this results in a reduction in PE content and a marked increase in DG and TG. Conversely, reduction of hepatic SAMe following the administration of a methionine-deficient diet reverted the flux from PE to PC of Gnmt-/- mice to that of wildtype animals and normalized DG and TG content preventing the development of steatosis. Gnmt-/- mice with an additional deletion of perilipin2, the predominant lipid droplet protein, maintain high SAMe levels, with a concurrent increased flux from PE to PC, but do not develop liver steatosis. Conclusion: These findings indicate that excess SAMe reroutes PE towards PC and TG synthesis and lipid sequestration. © 2013 by the American Association for the Study of Liver Diseases.

Martinez-Arranz I.,OWL | Mayo R.,OWL | Perez-Cormenzana M.,OWL | Minchole I.,OWL | And 3 more authors.
Journal of Proteomics | Year: 2015

Metabolomics research, like other disciplines utilizing high-throughput technologies, generates a large amount of data for every sample. Although handling this data is a challenge and one of the biggest bottlenecks of the metabolomics workflow, it is also the clue to accomplish valuable results. This work has been designed to supply methodological data mining guidelines, describing systematically the steps to be followed in metabolomics data exploration. Instrumental raw data refinement in the pre-processing step and assessment of the statistical assumptions in pre-treatment directly affect the results of subsequent univariate and multivariate analyses. A study of aging in a healthy population was selected to represent this data mining process. Multivariate analysis of variance and linear regression methods were used to analyze the metabolic changes underlying aging. Selection of both multivariate methods aims to illustrate the treatment of age from two rather different perspectives, as a categorical variable and a continuous variable. Biological significance: Metabolomics is a discipline involving the analysis of a large amount of data to gather relevant information. Researchers in this field have to overcome the challenges of complex data processing and statistical analysis issues. A wide range of tasks has to be executed, from the minimization of batch-to-batch/systematic variations in pre-processing, to the application of common data analysis techniques relying on statistical assumptions. In this work, a real-data metabolic profiling research on aging was used to illustrate the proposed workflow and suggest a set of guidelines for analyzing metabolomics data.This article is part of a Special Issue entitled: HUPO 2014. © 2015 Elsevier B.V.

Sot J.,University of the Basque Country | Manni M.M.,University of the Basque Country | Viguera A.R.,University of the Basque Country | Castaneda V.,University of the Basque Country | And 6 more authors.
Biophysical Journal | Year: 2014

The origin of resistance to detergent solubilization in certain membranes, or membrane components, is not clearly understood. We have studied the solubilization by Triton X-100 of binary mixtures composed of egg sphingomyelin (SM) and either ceramide, diacylglycerol, or cholesterol. Solubilization has been assayed in the 4-50°C range, and the results are summarized in a novel, to our knowledge, form of plots, that we have called temperature-solubilization diagrams. Despite using a large detergent excess (lipid/detergent 1:20 mol ratio) and extended solubilization times (24-48 h) certain mixtures were not amenable to Triton X-100 solubilization at one or more temperatures. DSC of all the lipid mixtures, and of all the lipid + detergent mixtures revealed that detergent resistance was associated with the presence of gel domains at the assay temperature. Once the system melted down, solubilization could occur. In general adding high-melting lipids limited the solubilization, whereas the addition of low-melting lipids promoted it. Lipidomic analysis of Madin-Darby canine kidney cell membranes and of the corresponding detergent-resistant fraction indicated a large enrichment of the nonsolubilized components in saturated diacylglycerol and ceramide. SM-cholesterol mixtures were special in that detergent solubilization was accompanied, for certain temperatures and compositions, by an independent phenomenon of reassembly of the partially solubilized lipid bilayers. The temperature at which lysis and reassembly prevailed was ∼25°C, thus for some SM-cholesterol mixtures solubilization occurred both above and below 25°C, but not at that temperature. These observations can be at the origin of the detergent resistance effects observed with cell membranes, and they also mean that cholesterol-containing detergent-resistant membrane remnants cannot correspond to structures existing in the native membrane before detergent addition. © 2014 Biophysical Society.

Cano A.,OWL | Alonso C.,OWL
Biochemical Society Transactions | Year: 2014

Non-alcoholic fatty liver disease (NAFLD) is one of themost common liver disorders in industrialized countries. NAFLD develops in the absence of alcohol abuse and encompasses a wide spectrum of disorders ranging from benign fatty liver to non-alcoholic steatohepatitis (NASH). NASH often leads to fibrosis, cirrhosis and, finally, hepatocellular carcinoma (HCC). Therefore the earlier NAFLD is diagnosed, the better the patient's outlook. A tightly connected basic and applied research is essential to find the molecular mechanisms that accompany illness and to translate them into the clinic. From the simple starting point for triacylglycerol (TG) accumulation in the liver to the more complex implications of phospholipids in membrane biophysics, the influence of lipids may be the clue to understand NAFLD pathophysiology. Nowadays, it is achievable to diagnose non-invasively the initial symptoms to stop, revert or even prevent disease development. In this context, merging metabolomics with other techniques and the interpretation of the huge information obtained resembles the 'Rosetta stone' to decipher the pathological metabolic fluxes that must be targeted to find a cure. In the present review, we have tackled the application of metabolomics to find out the metabolic fluxes that underlie membrane integrity in NAFLD. ©The Authors Journal compilation ©2014 Biochemical Society.

PubMed | OWL, IVI Valencia, IVI Seville and INCLIVA Biomedical Research and Fundacion IVI
Type: Journal Article | Journal: PloS one | Year: 2015

Despite efforts made to improve the in vitro embryo culture conditions used during assisted reproduction procedures, human embryos must adapt to different in vitro oxygen concentrations and the new metabolic milieu provided by the diverse culture media used for such protocols. It has been shown that the embryo culture environment can affect not only cellular metabolism, but also gene expression in different species of mammalian embryos. Therefore we wanted to compare the metabolic footprint left by human cleavage-stage embryos under two types of oxygen atmospheric culture conditions (6% and 20% O2). The spent culture media from 39 transferred and implanted embryos from a total of 22 patients undergoing egg donation treatment was analyzed; 23 embryos came from 13 patients in the 6% oxygen concentration group, and 16 embryos from 9 patients were used in the 20% oxygen concentration group. The multivariate statistics we used in our analysis showed that human cleavage-stage embryos grown under both types of oxygen concentration left a similar metabolic fingerprint. We failed to observe any change in the net depletion or release of relevant analytes, such as glucose and especially fatty acids, by human cleavage-stage embryos under either type of culture condition. Therefore it seems that low oxygen tension during embryo culture does not alter the global metabolism of human cleavage-stage embryos.

PubMed | OWL and University of the Basque Country
Type: | Journal: Chemistry and physics of lipids | Year: 2015

A comparative lipidomic study has been performed of whole Madin-Darby canine kidney epithelial cells and of the detergent-resistant membrane fraction (DRM) obtained after treating the cells with the non-ionic detergent Triton X-100. The DRM were isolated following a standard procedure that is extensively used in cell biology studies. Significant differences were found in the lipid composition of the whole cells and of DRM. The latter were enriched in all the analyzed sphingolipid classes: sphingomyelins, ceramides and hexosylceramides. Diacylglycerols were also preferentially found in DRM. The detergent-resistant fraction was also enriched in saturated over unsaturated fatty acyl chains, and in sn-1 acyl chains containing 16 carbon atoms, over the longer and shorter ones. The glycerophospholipid species phosphatidylethanolamines and phosphatidylinositols, that were mainly unsaturated, did not show a preference for DRM. Phosphatidylcholines were an intermediate case: the saturated, but not the unsaturated species were found preferentially in DRM. The question remains on whether these DRM, recovered from detergent-membrane mixtures by floatation over a sucrose gradient, really correspond to membrane domains existing in the cell membrane prior to detergent treatment.

PubMed | OWL, University of Barcelona, University of the Basque Country, CIBER ISCIII and 2 more.
Type: Journal Article | Journal: Oncotarget | Year: 2015

The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.

PubMed | OWL, Ikerbasque and CIBER ISCIII
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

Hepatocytes are involved in the endogenous and drug metabolism; many of the enzymes involved in those processes are incorporated into extracellular vesicles and secreted into the bloodstream. Liver-damaging conditions modify the molecular cargo of those vesicles significantly. However, no information about the effect of these hepatic vesicles on the extracellular environment is available. Drug-induced liver damage increases the number of circulating extracellular vesicles and affects the release and content of hepatocyte-derived vesicles. In this work, we evaluated the metabolic effect of these vesicles on the composition of the serum. We performed a targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics analysis of serum samples. The samples had been first incubated with hepatic extracellular vesicles from hepatocytes challenged with acetaminophen or diclofenac. The incubation affected the serum levels of 67 metabolites, such as amino acids and different species of lipids. The metabolites included various species of phosphatidylcholines and phosphatidylethanolamines. These compounds are the components of biological membranes; our observations suggest that the vesicles might take part in remodelling and maintenance of the membranes. Alterations in the levels of some other serum metabolites might have deleterious consequences, for example, the tetracosanoic acid with its cardiovascular effects. However, some of the metabolites whose levels were increased, including alpha-linoleic and tauroursodeoxycholic acids, have been reported to have a protective effect. Our targeted metabolomics analysis indicated that the hepatic extracellular vesicles act as nano-metabolic machines supplying the extracellular environment with the means to integrate diverse tissue responses. In conclusion, we show that the hepatic extracellular vesicles are metabolically active and might play a role in the physiopathological response to hepatic insults, including drug-induced liver injury.

Type: Journal Article | Journal: Liver international : official journal of the International Association for the Study of the Liver | Year: 2016

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare life-threatening liver disease that lacks a specific diagnostic test being frequently misdiagnosed as cryptogenic cirrhosis. Preliminary data from our group identified a plasma metabolomic profile able to differentiate INCPH from patients with cirrhosis (CH) and healthy volunteers (HV). However, the untargeted methodology applied was unable to identify all the specific metabolites, hampering the possibility of building-up diagnostic models. This study applies a wide-coverage of previously identified metabolites through a high-throughput metabolomics technology, evaluating if there is a metabolomic profile that allows a non-invasive diagnosis of INCPH.We included 34 patients with INCPH, 34 with CH and 34 HV. We performed a targeted metabolomic analysis of serum samples using UPLC-MS. The best combination of a set of specific metabolites was obtained using stepwise logistic regression (LR) and recursive partitioning analysis (RPA).After internal cross-validation, LR analysis identified a subset of 5-metabolites that clearly differentiate INCPH patients from CH and HV (average corrected optimism AUROC = 0.8871 [0.838-0.924]). Using high and low cut-off values the model has an excellent capacity to respectively diagnose or exclude INCPH. The RPA analysis strategy used the 3-metabolites signature differentiating INCPH from CH and the 2-metabolites signature differentiating INCPH from HV. A decision tree applying sequentially these metabolic profiles diagnosed 88% of INCPH patients.Different metabolomic profiles allow the diagnosis of INCPH with high specificity and sensibility and may represent excellent clinical tools for its diagnosis avoiding multiple and invasive tests.

News Article | October 29, 2016
Site: www.prweb.com

Technology Assurance Labs, announced today that it added a new OWL© 3G cellular radio for remote tank monitoring to complement OWL’s existing fixed wireless solution. The new radio will be unveiled at the upcoming November LPGas Summit Nov 14 -16 in Orlando, Florida. Ken Stauffer, Co-Founder of Technology Assurance Labs, explains “this is a great addition to OWL’s portfolio of wireless monitoring devices. The OWL© 3G radio is a low cost solution to monitor residential propane tanks and comes with an industry best, 10 year battery warranty.” The OWL© 3G cellular radio transmits tank level data daily to the dealer’s OWL© software portal which is accessed via any device (laptop, smartphone, or tablet) with a web browser or via an application programing interface (API) for back office systems. OWL© radios and software not only monitor tank usage, but also offer a “Pay As You Go” service. “Pay As You Go” allows dealers to invoice customers monthly based on real usage, thereby increasing the dealers’ ROI and winning competitive bids. OWL© About Technology Assurance Labs: Technology Assurance Labs, formed in March 2003, is a privately owned LLC headquartered in, Orlando, Fla. It is an independent laboratory, serving equipment vendors, venture capital groups, and service providers with services such as technology planning and management, network and system design, and technology testing. It has also developed RFID products for the rail industry and M2M wireless sensor products for the propane and gas metering industry. For more information please visit http://www.talabs.com. About OWL© Overhead Wireless Logic System, The OWL© 3G radio is a low cost solution to monitor residential propane tanks and comes with an industry best, 10 year battery warranty”over a given area using licensed spectrum. The first OWL© products developed are targeted to the propane and natural gas industry, but other sensors in development include temperature, liquid pressure, soil moisture, etc. http://www.owlsite.net

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