From the Institute for Genomics and Bioinformatics, Graz University of Technology, Petergasse 14, 8010 Graz, Austria.
J Biol Chem. 2013 Dec 13;288(50):36040-51. doi: 10.1074/jbc.M113.491324. Epub 2013 Oct 23.
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.
NAT8L（N-乙酰基转移酶 8 样）催化乙酰辅酶 A 和天冬氨酸形成 N-乙酰天门冬氨酸（NAA）。在大脑中，NAA 提供乙酰辅酶 A 合成所需的乙酰基，进一步用于脂肪酸生成。然而，其在其他组织中的功能仍不清楚。在这里，我们首次表明，Nat8l 在脂肪组织和鼠类及人类脂肪生成细胞系中高度表达，并定位于棕色脂肪细胞的线粒体中。在永生化棕色脂肪生成细胞中稳定过表达 Nat8l 可强烈增加葡萄糖掺入中性脂质，同时伴有脂解增加，表明脂质周转率加快。此外，线粒体质量和数量以及耗氧量在 Nat8l 过表达时升高。相应地，棕色标记基因（如 Prdm16、Cidea、Pgc1α、Pparα，特别是 UCP1）的表达水平在这些细胞中明显升高。用 PPARα 拮抗剂处理表明，UCP1 表达和耗氧量的增加依赖于 PPARα。在棕色脂肪细胞中敲低 Nat8l 对细胞内甘油三酯含量、脂肪生成或耗氧量没有影响，但脂解和棕色标记基因表达增加；在 Nat8l-KO 小鼠的 BAT 中也观察到这种情况。有趣的是，在沉默 Nat8l 的脂肪细胞和 Nat8l-KO 小鼠的 BAT 中，ATP-柠檬酸裂解酶的表达增加，表明存在一种补偿机制，以维持 Nat8l 水平降低后乙酰辅酶 A 池。总之，我们的数据表明 Nat8l 影响棕色脂肪生成表型，并提示存在 NAT8L 驱动的 NAA 代谢作为为脂肪细胞中脂质合成提供细胞质乙酰辅酶 A 的新途径。
