Dynamic Modification of Sphingomyelin in Lipid Microdomains Controls Development of Obesity, Fatty Liver, and Type 2 Diabetes
Dynamic Modification of Sphingomyelin in Lipid Microdomains Controls Development of Obesity, Fatty Liver, and Type 2 Diabetes
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DOI：
10.1074/jbc.m111.255646
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发表时间：
2011-08-12
影响因子：
4.8
通讯作者：
Igarashi, Yasuyuki
中科院分区：
文献类型：
--
作者：
Mitsutake, Susumu;Zama, Kota;Igarashi, Yasuyuki
脂质微区或小窝，质膜的小内陷，已成为脂质摄取和葡萄糖稳态的重要元素。鞘磷脂（SM）是脂质微区的主要磷脂之一。在这项研究中，我们使用SMS 2基因敲除小鼠研究了SMS 2的生理功能，我们发现SMS 2缺陷可预防高脂饮食诱导的肥胖和胰岛素抵抗。有趣的是，在SMS 2基因敲除小鼠的肝脏中，几乎没有观察到大而成熟的脂滴。用针对SMS 2的siRNA处理也减少了HepG 2细胞中的大脂滴。此外，SMS 2的siRNA降低了瘦素缺陷（ob/ob）小鼠肝脏中甘油三酯的积累，强烈表明SMS 2参与脂滴形成。此外，我们发现SMS 2存在于脂质微区中，并部分与脂肪酸转运蛋白CD 36/FAT和小窝支架蛋白Caveolin 1相关。由于CD 36/FAT和小窝蛋白1存在于脂质微区中并协同参与脂滴形成，因此SMS 2涉及脂质微区中SM的调节，导致CD 36/FAT和小窝的调节。在这里，我们建立了新的细胞系，在其中我们可以完全区分SMS 2活性和SMS 1活性，并且我们证明了SMS 2可以将质膜外叶中产生的神经酰胺转化为SM。我们的研究结果表明，新的和动态的调节脂质微结构域通过构象变化的脂质质膜上的SMS 2，这是负责肥胖和2型糖尿病。
Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as important elements for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelin synthase 2 (SMS2) using SMS2 knock-out mice, and we found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2 knock-out mice, large and mature lipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipid droplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplet formation. Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acid transporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Because CD36/FAT and caveolin 1 exist in lipid microdomains and are coordinately involved in lipid droplet formation, SMS2 is implicated in the modulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, we established new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and we demonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane into SM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformational changes in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes.