Rab8a Deficiency in Skeletal Muscle Causes Hyperlipidemia and Hepatosteatosis by Impairing Muscle Lipid Uptake and Storage
Rab8a Deficiency in Skeletal Muscle Causes Hyperlipidemia and Hepatosteatosis by Impairing Muscle Lipid Uptake and Storage
复制标题
骨骼肌中 Rab8a 缺陷通过损害肌肉脂质摄取和储存而导致高脂血症和肝脂肪变性
DOI：
10.2337/db17-0077
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发表时间：
2017-09-01
期刊：
影响因子：
7.7
通讯作者：
Chen, Shuai
中科院分区：
文献类型：
--
作者：
Chen, Qiaoli;Rong, Ping;Chen, Shuai
骨骼肌吸收长链脂肪酸(LCFA)，这些脂肪酸要么在线粒体中被氧化，要么以甘油三酯的形式暂时储存在脂滴(LDs)中。到目前为止，人们仍然不完全清楚肌肉中脂肪的吸收和储存是如何调节的，以及这些是否对全身脂肪的动态平衡很重要。在这里，我们展示了小的GTP酶Rab8a调节骨骼肌脂类的摄取和储存。肌肉特异的Rab8a缺失导致高脂血症，并加剧了高脂饮食诱导的肝骨病。在机制上，Rab8a缺乏减少了LCFA进入骨骼肌并抑制了肌细胞中的LD融合。结果，血脂水平升高，并刺激了肝脏哺乳动物雷帕霉素的靶标雷帕霉素，雷帕霉素通过上调肝脏脂肪生成和胆固醇生物合成而增强了肝脏骨质疏松症。我们的结果证明了肌肉中脂肪的摄取和储存在调节全身脂质平衡中的重要性，并揭示了骨骼肌在高脂血症和肝骨病发病机制中的作用。
Skeletal muscle absorbs long-chain fatty acids (LCFAs) that are either oxidized in mitochondria or temporarily stored as triglycerides in lipid droplets (LDs). So far, it is still not fully understood how lipid uptake and storage are regulated in muscle and whether these are important for whole-body lipid homeostasis. Here we show that the small GTPase Rab8a regulates lipid uptake and storage in skeletal muscle. Muscle-specific Rab8a deletion caused hyperlipidemia and exacerbated hepatosteatosis induced by a high-fat diet. Mechanistically, Rab8a deficiency decreased LCFA entry into skeletal muscle and inhibited LD fusion in muscle cells. Consequently, blood lipid levels were elevated and stimulated hepatic mammalian target of rapamycin, which enhanced hepatosteatosis by upregulating hepatic lipogenesis and cholesterol biosynthesis. Our results demonstrate the significance of lipid uptake and storage in muscle in regulating whole-body lipid homeostasis, and they shed light on the roles of skeletal muscle in the pathogenesis of hyperlipidemia and hepatosteatosis.