Rab8a Deficiency in Skeletal Muscle Causes Hyperlipidemia and Hepatosteatosis by Impairing Muscle Lipid Uptake and Storage.

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. © 2017 by the American Diabetes Association.

Citation

Qiaoli Chen, Ping Rong, Dijin Xu, Sangsang Zhu, Liang Chen, Bingxian Xie, Qian Du, Chao Quan, Yang Sheng, Tong-Jin Zhao, Peng Li, Hong Yu Wang, Shuai Chen. Rab8a Deficiency in Skeletal Muscle Causes Hyperlipidemia and Hepatosteatosis by Impairing Muscle Lipid Uptake and Storage. Diabetes. 2017 Sep;66(9):2387-2399

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PMID: 28696211

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