title: NAT8L (N-acetyltransferase 8-like) accelerates lipid turnover and increases energy expenditure in brown adipocytes.
abstract: NAT8L (N-acetyltransferase 8-like) catalyzes the formation of N-acetylaspartate (NAA) from acetyl-CoA and aspartate. In the brain, NAA delivers the acetate moiety for synthesis of acetyl-CoA that is further used for fatty acid generation. However, its function in other tissues remained elusive. Here, we show for the first time that Nat8l is highly expressed in adipose tissues and murine and human adipogenic cell lines and is localized in the mitochondria of brown adipocytes. Stable overexpression of Nat8l in immortalized brown adipogenic cells strongly increases glucose incorporation into neutral lipids, accompanied by increased lipolysis, indicating an accelerated lipid turnover. Additionally, mitochondrial mass and number as well as oxygen consumption are elevated upon Nat8l overexpression. Concordantly, expression levels of brown marker genes, such as Prdm16, Cidea, Pgc1α, Pparα, and particularly UCP1, are markedly elevated in these cells. Treatment with a PPARα antagonist indicates that the increase in UCP1 expression and oxygen consumption is PPARα-dependent. Nat8l knockdown in brown adipocytes has no impact on cellular triglyceride content, lipogenesis, or oxygen consumption, but lipolysis and brown marker gene expression are increased; the latter is also observed in BAT of Nat8l-KO mice. Interestingly, the expression of ATP-citrate lyase is increased in Nat8l-silenced adipocytes and BAT of Nat8l-KO mice, indicating a compensatory mechanism to sustain the acetyl-CoA pool once Nat8l levels are reduced. Taken together, our data show that Nat8l impacts on the brown adipogenic phenotype and suggests the existence of the NAT8L-driven NAA metabolism as a novel pathway to provide cytosolic acetyl-CoA for lipid synthesis in adipocytes.
authors.affiliation: From the Institute for Genomics and Bioinformatics, Graz University of Technology, Petergasse 14, 8010 Graz, Austria.
authors.forename: Ariane R
authors.initials: AR
authors.lastname: Pessentheiner
authors.forename: Helmut J
authors.initials: HJ
authors.lastname: Pelzmann
authors.forename: Evelyn
authors.initials: E
authors.lastname: Walenta
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.forename: Lukas N
authors.initials: LN
authors.lastname: Groschner
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Uno
authors.forename: Toh
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Dietmar
authors.initials: D
authors.lastname: Rieder
authors.forename: Andreas
authors.initials: A
authors.lastname: Prokesch
authors.forename: Juliane G
authors.initials: JG
authors.lastname: Bogner-Strauss
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052437:Adipocytes, Brown / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D004734:Energy Metabolism; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D053142:Mitochondrial Size; D047493:PPAR alpha / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D021381:Protein Transport; D000071256:Uncoupling Protein 1; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D007473:Ion Channels; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D010750:Phosphoproteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C104434:spindlin; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; C116373:NAT8 protein, human; D011494:Protein Kinases; C032202:ATP-citrate lyase kinase
keywords: Acetyl Coenzyme A; Adipose Tissue Metabolism; Aspartate; Brown Adipocytes; Energy Expenditure; Fatty Acid Metabolism; Lipid Metabolism; N-Acetylaspartate; N-Acetyltransferase 8-like