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Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism

Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study...

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Autores principales: Heier, Christoph, Taschler, Ulrike, Radulovic, Maja, Aschauer, Philip, Eichmann, Thomas O., Grond, Susanne, Wolinski, Heimo, Oberer, Monika, Zechner, Rudolf, Kohlwein, Sepp D., Zimmermann, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2016
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882453/
https://www.ncbi.nlm.nih.gov/pubmed/27036938
http://dx.doi.org/10.1074/jbc.M115.705541
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author Heier, Christoph
Taschler, Ulrike
Radulovic, Maja
Aschauer, Philip
Eichmann, Thomas O.
Grond, Susanne
Wolinski, Heimo
Oberer, Monika
Zechner, Rudolf
Kohlwein, Sepp D.
Zimmermann, Robert
author_facet Heier, Christoph
Taschler, Ulrike
Radulovic, Maja
Aschauer, Philip
Eichmann, Thomas O.
Grond, Susanne
Wolinski, Heimo
Oberer, Monika
Zechner, Rudolf
Kohlwein, Sepp D.
Zimmermann, Robert
author_sort Heier, Christoph
collection PubMed
description Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study, we used a biochemical screen in Saccharomyces cerevisiae to identify and characterize putative hydrolases involved in FAEE catabolism. We found that Yju3p, the functional orthologue of mammalian monoacylglycerol lipase (MGL), contributes >90% of cellular FAEE hydrolase activity, and its loss leads to the accumulation of FAEE. Heterologous expression of mammalian MGL in yju3Δ mutants restored cellular FAEE hydrolase activity and FAEE catabolism. Moreover, overexpression or pharmacological inhibition of MGL in mouse AML-12 hepatocytes decreased or increased FAEE levels, respectively. FAEEs were transiently incorporated into lipid droplets (LDs) and both Yju3p and MGL co-localized with these organelles. We conclude that the storage of FAEE in inert LDs and their mobilization by LD-resident FAEE hydrolases facilitate a controlled metabolism of these potentially toxic lipid metabolites.
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spelling pubmed-48824532016-06-02 Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism Heier, Christoph Taschler, Ulrike Radulovic, Maja Aschauer, Philip Eichmann, Thomas O. Grond, Susanne Wolinski, Heimo Oberer, Monika Zechner, Rudolf Kohlwein, Sepp D. Zimmermann, Robert J Biol Chem Lipids Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study, we used a biochemical screen in Saccharomyces cerevisiae to identify and characterize putative hydrolases involved in FAEE catabolism. We found that Yju3p, the functional orthologue of mammalian monoacylglycerol lipase (MGL), contributes >90% of cellular FAEE hydrolase activity, and its loss leads to the accumulation of FAEE. Heterologous expression of mammalian MGL in yju3Δ mutants restored cellular FAEE hydrolase activity and FAEE catabolism. Moreover, overexpression or pharmacological inhibition of MGL in mouse AML-12 hepatocytes decreased or increased FAEE levels, respectively. FAEEs were transiently incorporated into lipid droplets (LDs) and both Yju3p and MGL co-localized with these organelles. We conclude that the storage of FAEE in inert LDs and their mobilization by LD-resident FAEE hydrolases facilitate a controlled metabolism of these potentially toxic lipid metabolites. American Society for Biochemistry and Molecular Biology 2016-05-27 2016-03-31 /pmc/articles/PMC4882453/ /pubmed/27036938 http://dx.doi.org/10.1074/jbc.M115.705541 Text en © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Lipids
Heier, Christoph
Taschler, Ulrike
Radulovic, Maja
Aschauer, Philip
Eichmann, Thomas O.
Grond, Susanne
Wolinski, Heimo
Oberer, Monika
Zechner, Rudolf
Kohlwein, Sepp D.
Zimmermann, Robert
Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism
title Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism
title_full Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism
title_fullStr Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism
title_full_unstemmed Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism
title_short Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism
title_sort monoacylglycerol lipases act as evolutionarily conserved regulators of non-oxidative ethanol metabolism
topic Lipids
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882453/
https://www.ncbi.nlm.nih.gov/pubmed/27036938
http://dx.doi.org/10.1074/jbc.M115.705541
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