核苷二磷酸激酶1和2在高脂饮食下调节肝脏的保护性反应。
Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet.
发表日期：2023 Sep 08
作者：
Domenico Iuso, Isabel Garcia-Saez, Yohann Couté, Yoshiki Yamaryo-Botté, Elisabetta Boeri Erba, Annie Adrait, Nour Zeaiter, Malgorzata Tokarska-Schlattner, Zuzana Macek Jilkova, Fayçal Boussouar, Sophie Barral, Luca Signor, Karine Couturier, Azadeh Hajmirza, Florent Chuffart, Ekaterina Bourova-Flin, Anne-Laure Vitte, Lisa Bargier, Denis Puthier, Thomas Decaens, Sophie Rousseaux, Cyrille Botté, Uwe Schlattner, Carlo Petosa, Saadi Khochbin
来源：
Epigenetics & Chromatin
摘要：
从乙酰辅酶A（AcCoA）合成脂肪酸在多种疾病（包括癌症）中发生了异常调节。本文报告核苷酸二磷酸激酶1和2号（NME1/2），这些参与核苷酸平衡的家庭酶最近被发现与辅酶A结合。我们展示NME1还与AcCoA结合，并且配体识别牵涉到CoA/AcCoA 3'磷酸依赖的独特结合方式。我们报告了Nme2基因敲除小鼠在高脂饮食下的过度三酰甘油合成和肝脏脂肪变性。在肝细胞中，NME2介导HFD所导致的基因转录反应，导致脂肪酸积累的抑制和保护基因表达计划的激活，通过靶向组蛋白乙酰化实现。我们的发现将NME1/2与HFD防护性肝脏应答的表观遗传调控联系起来，并暗示其在控制组蛋白乙酰化和脂肪酸合成之间的竞争性AcCoA使用中可能发挥潜在作用。
The synthesis of fatty acids from acetyl-coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3' phosphate. We report that Nme2 knockout mice fed a high-fat diet (HFD) exhibit excessive triglyceride synthesis and liver steatosis. In liver cells, NME2 mediates a gene transcriptional response to HFD leading to the repression of fatty acid accumulation and activation of a protective gene expression program via targeted histone acetylation. Our findings implicate NME1/2 in the epigenetic regulation of a protective liver response to HFD and suggest a potential role in controlling AcCoA usage between the competing paths of histone acetylation and fatty acid synthesis.