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      Chronic Alcohol Exposure Disturbs Lipid Homeostasis at the Adipose Tissue-Liver Axis in Mice: Analysis of Triacylglycerols Using High-Resolution Mass Spectrometry in Combination with In Vivo Metabolite Deuterium Labeling


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          A method of employing high-resolution mass spectrometry in combination with in vivo metabolite deuterium labeling was developed in this study to investigate the effects of alcohol exposure on lipid homeostasis at the white adipose tissue (WAT)-liver axis in a mouse model of alcoholic fatty liver. In order to differentiate the liver lipids synthesized from the fatty acids that were transported back from adipose tissue and the lipids synthesized from other sources of fatty acids, a two-stage mouse feeding experiment was performed to incorporate deuterium into metabolites. Hepatic lipids extracted from mouse liver, epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (sWAT) were analyzed. It was found that 13 and 10 triacylglycerols (TGs) incorporated with a certain number of deuterium were significantly increased in alcohol induced fatty liver at two and four weeks of alcohol feeding periods, respectively. The concentration changes of these TGs ranged from 1.7 to 6.3-fold increase. A total of 14 deuterated TGs were significantly decreased in both eWAT and sWAT at the two and four weeks and the fold-change ranged from 0.19 to 0.77. The increase of deuterium incorporated TGs in alcohol-induced fatty liver and their decrease in both eWAT and sWAT indicate that alcohol exposure induces hepatic influx of fatty acids which are released from WATs. The results of time course analysis further indicate a mechanistic link between adipose fat loss and hepatic fat gain in alcoholic fatty liver.

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          Most cited references21

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          Detecting differential gene expression with a semiparametric hierarchical mixture method.

          Mixture modeling provides an effective approach to the differential expression problem in microarray data analysis. Methods based on fully parametric mixture models are available, but lack of fit in some examples indicates that more flexible models may be beneficial. Existing, more flexible, mixture models work at the level of one-dimensional gene-specific summary statistics, and so when there are relatively few measurements per gene these methods may not provide sensitive detectors of differential expression. We propose a hierarchical mixture model to provide methodology that is both sensitive in detecting differential expression and sufficiently flexible to account for the complex variability of normalized microarray data. EM-based algorithms are used to fit both parametric and semiparametric versions of the model. We restrict attention to the two-sample comparison problem; an experiment involving Affymetrix microarrays and yeast translation provides the motivating case study. Gene-specific posterior probabilities of differential expression form the basis of statistical inference; they define short gene lists and false discovery rates. Compared to several competing methodologies, the proposed methodology exhibits good operating characteristics in a simulation study, on the analysis of spike-in data, and in a cross-validation calculation.
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            Chronic alcohol exposure stimulates adipose tissue lipolysis in mice: role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis.

            Alcohol consumption induces liver steatosis; therefore, this study investigated the possible role of adipose tissue dysfunction in the pathogenesis of alcoholic steatosis. Mice were pair-fed an alcohol or control liquid diet for 8 weeks to evaluate the alcohol effects on lipid metabolism at the adipose tissue-liver axis. Chronic alcohol exposure reduced adipose tissue mass and adipocyte size. Fatty acid release from adipose tissue explants was significantly increased in alcohol-fed mice in association with the activation of adipose triglyceride lipase and hormone-sensitive lipase. Alcohol exposure induced insulin intolerance and inactivated adipose protein phosphatase 1 in association with the up-regulation of phosphatase and tensin homolog (PTEN) and suppressor of cytokine signaling 3 (SOCS3). Alcohol exposure up-regulated fatty acid transport proteins and caused lipid accumulation in the liver. To define the mechanistic link between adipose triglyceride loss and hepatic triglyceride gain, mice were first administered heavy water for 5 weeks to label adipose triglycerides with deuterium, and then pair-fed alcohol or control diet for 2 weeks. Deposition of deuterium-labeled adipose triglycerides in the liver was analyzed using Fourier transform ion cyclotron mass spectrometry. Alcohol exposure increased more than a dozen deuterium-labeled triglyceride molecules in the liver by up to 6.3-fold. These data demonstrate for the first time that adipose triglycerides due to alcohol-induced hyperlipolysis are reverse transported and deposited in the liver. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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              Metabolism of lipids in human white adipocyte.

              Adipose tissue is considered as the body's largest storage organ for energy in the form of triacylglycerols, which are mobilized through lipolysis process, to provide fuel to other organs and to deliver substrates to liver for gluconeogenesis (glycerol) and lipoprotein synthesis (free fatty acids). The release of glycerol and free fatty acids from human adipose tissue is mainly dependent on hormone-sensitive lipase which is intensively regulated by hormones and agents, such as insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). A special attention is paid to the recently discovered perilipins which could regulate the activity of the lipase hormono-sensible. Most of the plasma triacylglycerols are provided by dietary lipids, secreted from the intestine in the form of chylomicron or from the liver in the form of VLDL. Released into circulation as non-esterified fatty acids by lipoprotein lipase, those are taken up by adipose tissue via specific plasma fatty acid transporters (CD36, FATP, FABPpm) and used for triacylglycerol synthesis. A small part of triacylglycerols is synthesized into adipocytes from carbohydrates (lipogenesis) but its regulation is still debated in human. Physiological factors such as dieting/fasting regulate all these metabolic pathways, which are also modified in pathological conditions e.g. obesity.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                6 February 2013
                : 8
                : 2
                : e55382
                [1 ]Chemistry Department, University of Louisville, Louisville, Kentucky, United States of America
                [2 ]Medicine Department, University of Louisville, Louisville, Kentucky, United States of America
                [3 ]Bioinformatics and Biostatistics Department, University of Louisville, Louisville, Kentucky, United States of America
                [4 ]Pharmacology & Toxicology Department, University of Louisville, Louisville, Kentucky, United States of America
                [5 ]Alcohol Research Center, University of Louisville, Louisville, Kentucky, United States of America
                [6 ]Robley Rex Louisville VAMC, Louisville, Kentucky, United States of America
                [7 ]Center for Translational Biomedical Research and Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina, United States of America
                National Institutes of Health, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ZZ XZ CJM. Performed the experiments: YT XS XY BB WZ YZ. Analyzed the data: XW WS SK. Contributed reagents/materials/analysis tools: XY BB. Wrote the paper: XW CJM ZZ XZ.

                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 29 October 2012
                : 21 December 2012
                Page count
                Pages: 10
                This work was supported by National Institutes of Health grants 1R01GM087735, R01AA018844, 1RC2AA019385, P01AA017103, P30AA019360, R01AA015970, R37AA010762, R01AA018016, R01AA018869, R01DK7071765, and Veteran’s Affairs. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Fatty Acids
                Model Organisms
                Animal Models
                Gastroenterology and Hepatology
                Liver Diseases
                Alcoholic Liver Disease
                Public Health



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