Department of Molecular Biology, University of Cantabria, IDIVAL, Santander, Spain.
Department of Internal Medicine, Hospital U.M. Valdecilla-IDIVAL, University of Cantabria, RETICEF, Santander, Spain.
Biochem Biophys Res Commun. 2014 Apr 4;446(2):614-9. doi: 10.1016/j.bbrc.2014.03.010. Epub 2014 Mar 12.
NR5A2 is a nuclear receptor which regulates the expression of genes involved in cholesterol metabolism, pluripotency maintenance and cell differentiation. It has been recently shown that DLPC, a NR5A2 ligand, prevents liver steatosis and improves insulin sensitivity in mouse models of insulin resistance, an effect that has been associated with changes in glucose and fatty acids metabolism in liver. Because skeletal muscle is a major tissue in clearing glucose from blood, we studied the effect of the activation of NR5A2 on muscle metabolism by using cultures of C2C12, a mouse-derived cell line widely used as a model of skeletal muscle. Treatment of C2C12 with DLPC resulted in increased levels of expression of GLUT4 and also of several genes related to glycolysis and glycogen metabolism. These changes were accompanied by an increased glucose uptake. In addition, the activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions. Our results suggest that NR5A2, mostly by enhancing glucose uptake, switches muscle cells into a state of glucose preference. The increased use of glucose by muscle might constitute another mechanism by which NR5A2 improves blood glucose levels and restores insulin sensitivity.
NR5A2 是一种核受体，它可以调节参与胆固醇代谢、多能性维持和细胞分化的基因的表达。最近已经表明，NR5A2 的配体 DLPC 可以预防胰岛素抵抗小鼠模型中的肝脂肪变性并改善胰岛素敏感性，这种作用与肝脏中葡萄糖和脂肪酸代谢的变化有关。因为骨骼肌是清除血液中葡萄糖的主要组织，我们使用 C2C12 细胞培养物研究了 NR5A2 的激活对肌肉代谢的影响，C2C12 是一种广泛用作骨骼肌模型的小鼠衍生细胞系。用 DLPC 处理 C2C12 会导致 GLUT4 的表达水平升高，同时还会导致与糖酵解和糖原代谢相关的几个基因的表达水平升高。这些变化伴随着葡萄糖摄取的增加。此外，NR5A2 的激活会导致脂肪酸的氧化减少，但在低糖条件下这种作用会消失。我们的结果表明，NR5A2 主要通过增强葡萄糖摄取，将肌肉细胞转变为葡萄糖偏好状态。肌肉对葡萄糖的利用增加可能是 NR5A2 降低血糖水平和恢复胰岛素敏感性的另一种机制。
