de Preux Anne-Sophie, Goosen Katinka, Zhang Weixian, Sima Anders A F, Shimano Hitoshi, Ouwens D Margriet, Diamant Michaela, Hillebrands Jan-Luuk, Rozing Jan, Lemke Greg, Beckmann Jacques S, Smit August B, Verheijen Mark H G, Chrast Roman
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Mol Cell Neurosci. 2007 Aug;35(4):525-34. doi: 10.1016/j.mcn.2007.04.010. Epub 2007 May 1.
Our previous work demonstrated that the sterol response element binding proteins (SREBP)-1 and SREBP-2, which are the key regulators of storage lipid and cholesterol metabolism respectively, are highly expressed in Schwann cells of adult peripheral nerves. In order to evaluate the role of Schwann cell SREBPs in myelination and functioning of peripheral nerves we have determined their expression during development, after fasting and refeeding, and in a rodent model of diabetes. Our results show that SREBP-1c and SREBP-2, unlike SREBP-1a, are the major forms of SREBPs present in peripheral nerves. The expression profile of SREBP-2 follows the expression of genes involved in cholesterol biosynthesis, while SREBP-1c is co-expressed with genes involved in storage lipid metabolism. In addition, the expression of SREBP-1c in the endoneurial compartment of peripheral nerves depends on nutritional status and is disturbed in type 1 diabetes. In line with this, insulin elevates the expression of SREBP-1c in primary cultured Schwann cells by activating the SREBP-1c promoter. Taken together, these findings reveal that SREBP-1c expression in Schwann cells responds to metabolic stimuli including insulin and that this response is affected in type 1 diabetes mellitus. This suggests that disturbed SREBP-1c regulated lipid metabolism may contribute to the pathophysiology of diabetic peripheral neuropathy.
我们之前的研究表明，固醇调节元件结合蛋白（SREBP）-1和SREBP-2分别是储存脂质和胆固醇代谢的关键调节因子，在成年外周神经的施万细胞中高度表达。为了评估施万细胞SREBPs在周围神经髓鞘形成和功能中的作用，我们测定了它们在发育过程中、禁食和再喂养后以及糖尿病啮齿动物模型中的表达。我们的结果表明，与SREBP-1a不同，SREBP-1c和SREBP-2是外周神经中SREBPs的主要形式。SREBP-2的表达谱与参与胆固醇生物合成的基因表达一致，而SREBP-1c与参与储存脂质代谢的基因共表达。此外，外周神经内膜区室中SREBP-1c的表达取决于营养状况，且在1型糖尿病中受到干扰。与此一致的是，胰岛素通过激活SREBP-1c启动子来提高原代培养的施万细胞中SREBP-1c的表达。综上所述，这些发现揭示了施万细胞中SREBP-1c的表达对包括胰岛素在内的代谢刺激有反应，且这种反应在1型糖尿病中受到影响。这表明SREBP-1c调节的脂质代谢紊乱可能导致糖尿病性周围神经病变的病理生理学。
