Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human Arterial Endothelial Cells.
Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human Arterial Endothelial Cells.
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DOI：
10.1074/jbc.m115.684274
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发表时间：
2015-10-16
期刊：
影响因子：
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通讯作者：
Toyoda M
中科院分区：
文献类型：
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作者：
Sasaki N;Itakura Y;Toyoda M
背景：神经节苷脂在衰老内皮细胞（EC）中的作用尚不清楚。结果：神经节苷脂 GM1 在衰老和衰老的 EC 上增加。 GM1 会导致 EC 中胰岛素信号传导受损。结论：GM1 随着衰老和老化而增加，导致 EC 中的胰岛素抵抗。意义：GM1 是第一个已知的导致 EC 胰岛素抵抗的因素。血管内皮细胞（EC）在血管的重要生理功能中发挥着核心作用，并有助于维持血管的完整性。因此，认为EC功能受损会导致血管疾病的发生。然而，伴随衰老和老化的EC功能障碍的分子机制尚未阐明。主要存在于细胞表面的糖复合物（例如糖蛋白、糖鞘脂和蛋白聚糖）携带的碳水化合物抗原不仅充当标记分子，而且充当功能分子。在这项研究中，我们研究了衰老和衰老过程中人类内皮细胞中鞘糖脂的丰度和功能作用。在鞘糖脂中，神经节苷脂 GM1 在复制性和过早衰老的 EC 以及来自老年受试者的 EC 的表面上大量表达。调节内皮细胞重要功能的胰岛素信号传导在衰老和老化的内皮细胞中受到损害。实际上，通过下调衰老 EC 上的 GM1 并使非衰老 EC 上的外源 GM1 过载，我们发现 GM1 丰度的增加在功能上会导致 EC 中胰岛素信号传导受损。总而言之，这些发现提供了第一个证据，表明在细胞衰老和衰老的条件下，GM1 在 EC 细胞表面丰度增加，并导致 EC 胰岛素抵抗。 GM1 可能是检测、预防和治疗胰岛素抵抗和相关血管疾病（尤其是老年人）的一个有吸引力的靶点。
Background: The roles of gangliosides in senescent endothelial cells (ECs) were unknown. Results: Ganglioside GM1 increased on senescent and aged ECs. GM1 contributes to the impairment of insulin signaling in ECs. Conclusion: Increased GM1 with senescence and aging contributes to insulin resistance in ECs. Significance: GM1 is the first known contributor to insulin resistance in ECs. Vascular endothelial cells (ECs) play central roles in physiologically important functions of blood vessels and contribute to the maintenance of vascular integrity. Therefore, it is considered that the impairment of EC functions leads to the development of vascular diseases. However, the molecular mechanisms of the EC dysfunctions that accompany senescence and aging have not yet been clarified. The carbohydrate antigens carried by glycoconjugates (e.g. glycoproteins, glycosphingolipids, and proteoglycans) mainly present on the cell surface serve not only as marker molecules but also as functional molecules. In this study, we have investigated the abundance and functional roles of glycosphingolipids in human ECs during senescence and aging. Among glycosphingolipids, ganglioside GM1 was highly expressed in abundance on the surface of replicatively and prematurely senescent ECs and also of ECs derived from an elderly subject. Insulin signaling, which regulates important functions of ECs, is impaired in senescent and aged ECs. Actually, by down-regulating GM1 on senescent ECs and overloading exogenous GM1 onto non-senescent ECs, we showed that an increased abundance of GM1 functionally contributes to the impairment of insulin signaling in ECs. Taken together, these findings provide the first evidence that GM1 increases in abundance on the cell surface of ECs under the conditions of cellular senescence and aging and causes insulin resistance in ECs. GM1 may be an attractive target for the detection, prevention, and therapy of insulin resistance and related vascular diseases, particularly in older people.