title: N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes.
abstract: Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression, and oxygen consumption. Combinations of approaches to increase intracellular NAA levels showed additive effects on lipolysis and gene repression, nearly abolishing the expression of Ucp1, Cidea, Prdm16, and Ppara. Transcriptome analyses of aspartoacylase knock-down cells indicate deficiencies in acetyl-CoA and lipid metabolism. Concordantly, cytoplasmic acetyl-CoA levels and global histone H3 acetylation were decreased. Further, activating histone marks (H3K27ac and H3K9ac) in promoters/enhancers of brown marker genes showed reduced acetylation status. Taken together, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. Thereby, we mechanistically connect the NAA pathway to the epigenomic regulation of gene expression, modulating the phenotype of brown adipocytes.
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Austria.|Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Prokesch
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Austria.
authors.forename: H J
authors.initials: HJ
authors.lastname: Pelzmann
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Austria.
authors.forename: A R
authors.initials: AR
authors.lastname: Pessentheiner
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Huber
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: C T
authors.initials: CT
authors.lastname: Madreiter-Sokolowski
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Drougard
authors.affiliation: Research Unit Functional Proteomics and Metabolic Pathways, Institute of Pathology, Medical University of Graz and Omics Center Graz, BioTechMed-Graz, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Schittmayer
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Austria.|ZMF, Center for Medical Research, Medical University of Graz, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Kolb
authors.affiliation: HEALTH Insitute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Magnes
authors.affiliation: HEALTH Insitute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Trausinger
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: W F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Research Unit Functional Proteomics and Metabolic Pathways, Institute of Pathology, Medical University of Graz and Omics Center Graz, BioTechMed-Graz, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Birner-Gruenberger
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: J A
authors.initials: JA
authors.lastname: Pospisilik
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Austria.
authors.forename: J G
authors.initials: JG
authors.lastname: Bogner-Strauss
mesh_terms: D000085:Acetates / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D052437:Adipocytes, Brown / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D006657:Histones / Q000737:chemistry*; D050356:Lipid Metabolism; D008066:Lipolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000085:Acetates; D006657:Histones; D014157:Transcription Factors; D001224:Aspartic Acid; D000105:Acetyl Coenzyme A; C000179:N-acetylaspartate