CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondria! Fragmentation in Obesity
CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondria! Fragmentation in Obesity
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DOI：
10.1016/j.cell.2019.05.008
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发表时间：
2019-05-30
期刊：
影响因子：
64.5
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
--
作者：
Hammerschmidt, Philipp;Ostkotte, Daniela;Bruening, Jens C.
异位脂肪沉积和线粒体改变！动力学有助于肥胖和胰岛素抵抗的发展。然而，这些过程之间的机械联系仍然不清楚。在这里，我们证明了合成神经酰胺合成酶的C-16：0鞘磷脂CerS5和CerS6影响不同的鞘脂池，并且取消CerS6而不是CerS5可以保护肥胖和胰岛素抵抗。我们确定了与来源于CerS5或CerS6的C-16：0鞘脂特异相互作用的蛋白质。在这里，只有CerS6衍生的C-16：0鞘脂结合线粒体裂变因子(MFF)。CerS6和MFF缺乏在体外保护脂肪酸诱导的线粒体断裂，这两种蛋白在体内肥胖诱导的线粒体中存在基因上的相互作用！胰岛素抵抗的碎片化和发展。我们的实验揭示了鞘脂信号依赖于特定的合成酶的前所未有的特异性，提供了肥胖患者肝脏脂肪沉积和线粒体碎裂之间的机制联系，并将CerS6衍生的鞘脂/MFF相互作用定义为代谢性疾病的治疗靶点。
Ectopic lipid deposition and altered mitochondria! dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C-16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C-16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C-16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondria' fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondria! fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.