Activation of liver X receptors promotes lipid accumulation but does not alter insulin action in human skeletal muscle cells
Activation of liver X receptors promotes lipid accumulation but does not alter insulin action in human skeletal muscle cells
复制标题
DOI：
10.1007/s00125-006-0140-8
复制
发表时间：
2006-05-01
期刊：
影响因子：
8.2
通讯作者：
Vidal, H
中科院分区：
文献类型：
--
作者：
Cozzone, D;Debard, C;Vidal, H
目的/假设：本研究的目的是探讨肝脏X受体（LXR）激活对脂质代谢和胰岛素作用的影响，在人骨骼肌细胞制备的对照组和2型diabetes.Subjects和方法：培养肌管肌肉活检的11瘦，健康对照组和10例2型糖尿病患者。通过RT-定量PCR检测LXR亚型和脂肪生成基因的mRNA水平，并通过蛋白激酶B丝氨酸473磷酸化和糖原合成测定评价LXR激动剂对胰岛素作用的影响。LXR α和LXR β在人骨骼肌和脂肪组织中均有表达，与对照组相比，2型糖尿病患者组织中LXR α和LXR β的mRNA丰度无差异。与控制对象。在培养的肌肉细胞中，T0901317激活LXR可显著增加编码脂肪生成酶（包括固醇调节元件结合蛋白1c、脂肪酸合酶和硬脂酰辅酶A去饱和酶1）的基因表达，并在高葡萄糖浓度下促进甘油三酯蓄积。重要的是，这些对脂质代谢的影响并不影响胰岛素对蛋白激酶B的激活。此外，LXR激动剂没有修改2型diabetes.Conclusions/interpretation患者的肌肉细胞中的胰岛素作用：这些数据表明，LXR激动剂可能会导致增加利用的脂质和葡萄糖在肌肉细胞中，而不影响胰岛素的作用机制。然而，在开发有效的基于LXR的治疗剂之前，应评估肌肉中甘油三酯蓄积的长期后果。
Aims/hypothesis: The aim of this study was to investigate the effects of liver X receptor (LXR) activation on lipid metabolism and insulin action in human skeletal muscle cells prepared from control subjects and from patients with type 2 diabetes.Subjects and methods: Cultured myotubes were obtained from muscle biopsies of 11 lean, healthy control subjects and ten patients with type 2 diabetes. The mRNA levels of LXR isoforms and lipogenic genes were estimated by RT-quantitative PCR, and the effects of LXR agonists on insulin action were evaluated by assays of protein kinase B serine 473 phosphorylation and glycogen synthesis.Results: Both LXR alpha and LXR beta were expressed in human skeletal muscle and adipose tissue and there was no difference in their mRNA abundance in tissues from patients with type 2 diabetes compared with control subjects. In cultured muscle cells, LXR activation by T0901317 strongly increased expression of the genes encoding lipogenic enzymes, including sterol regulatory element binding protein 1c, fatty acid synthase and stearoyl-CoA desaturase 1, and also promoted triglyceride accumulation in the presence of a high glucose concentration. Importantly, these effects on lipid metabolism did not affect protein kinase B activation by insulin. Furthermore, LXR agonists did not modify insulin action in muscle cells from patients with type 2 diabetes.Conclusions/interpretation:These data suggest that LXR agonists may lead to increased utilisation of lipids and glucose in muscle cells without affecting the mechanism of action of insulin. However, the long-term consequences of triglyceride accumulation in muscle should be evaluated before the development of effective LXR-based therapeutic agents.