N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes.

Andreas Prokesch, Helmut Josef Pelzmann, Ariane Pessentheiner, Katharina Huber, Corina Madreiter-Sokolowski, Anne Drougard, Matthias Schittmayer, Dagmar Kolb, Christoph Magnes, Gert Trausinger, Wolfgang Graier, Ruth Birner-Gruenberger, J Andrew Pospisilik, Juliane Gertrude Bogner-Strauß

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Number of pages12
JournalScientific Reports
Issue number6
Publication statusPublished - 5 Apr 2016

Keywords

  • N-acetylaspartate
  • Aspartoacylase
  • acetyl-CoA
  • metabolism
  • epigenetics

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