NAT8L (N-Acetyltransferase 8-Like) Accelerates Lipid Turnover and Increases Energy Expenditure in Brown Adipocytes

作者：Pessentheiner Ariane R; Pelzmann Helmut J; Walenta Evelyn; Schweiger Martina; Groschner Lukas N; Graier Wolfgang F; Kolb Dagmar; Uno Kyosuke; Miyazaki Toh; Nitta Atsumi; Rieder Dietmar; Prokesch Andreas; Bogner Strauss Juliane G^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(50): 36040-36051.

DOI：10.1074/jbc.M113.491324

• Acetyl Coenzyme A
• Adipose Tissue Metabolism
• Aspartate
• Fatty Acid Metabolism
• Lipid Metabolism
• Brown Adipocytes
• N-Acetylaspartate
• N-Acetyltransferase 8-like
• Energy Expenditure

Background: NAT8L (N-acetyltransferase 8-like) synthesizes N-acetylaspartate and is required for myelination in the brain. Its function in other tissues was undefined. Results:Nat8l is highly expressed in adipose tissues and impacts adipogenic marker gene expression, lipid turnover, and energy metabolism in brown adipocytes. Conclusion:Nat8l expression influences cellular bioenergetics in adipocytes. Significance: These findings establish a novel pathway in brown adipocyte metabolism. %26lt;br%26gt;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, Pgc1, Ppar, and particularly UCP1, are markedly elevated in these cells. Treatment with a PPAR antagonist indicates that the increase in UCP1 expression and oxygen consumption is PPAR-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.

• 出版日期2013-12-13