title: Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism.
abstract: 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.
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and christoph.heier@uni-graz.at.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heier
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Taschler
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Maja
authors.initials: M
authors.lastname: Radulovic
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Philip
authors.initials: P
authors.lastname: Aschauer
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grond
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and BioTechMed-Graz, 8010 Graz, Austria.
authors.forename: Heimo
authors.initials: H
authors.lastname: Wolinski
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Monika
authors.initials: M
authors.lastname: Oberer
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and BioTechMed-Graz, 8010 Graz, Austria.
authors.forename: Sepp D
authors.initials: SD
authors.lastname: Kohlwein
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz and robert.zimmermann@uni-graz.at.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D000431:Ethanol / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D029701:Saccharomyces cerevisiae Proteins; D000431:Ethanol; D008994:Monoacylglycerol Lipases; C552818:Yju3 protein, S cerevisiae
keywords: Saccharomyces cerevisiae; ethanol metabolism; fatty acid metabolism; lipid droplet; lipid metabolism; monoacylglycerol lipase; serine esterase