Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest
Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest
复制标题
肝脏 X 受体的激活通过细胞周期停滞抑制胰岛 β 细胞增殖
DOI：
10.1007/s00125-008-1174-x
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发表时间：
2009-01-01
期刊：
影响因子：
8.2
通讯作者：
Han, X.
中科院分区：
文献类型：
--
作者：
Meng, Z. X.;Nie, J.;Han, X.
目的/假设肝脏X受体（LXRs）是几种细胞类型中脂质稳态和增殖的重要转录调节因子。然而，LXR在胰腺β细胞中的作用尚未完全确定。本研究的目的是探讨LXRs对胰腺β细胞增殖的影响。瞬时转染和报告基因测定用于确定LXR在胰腺β细胞中的转录活性。使用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四氮唑（MTT）、DNA荧光测定、BrdU标记和[3 H]胸苷掺入测定来分析细胞活力和增殖。流式细胞仪分析细胞周期分布。结果发现Lxr α（也称为Nr 1h 3）和Lxr β（也称为Nr 1h 2）在HIT-T15和MIN 6细胞中均表达并反式激活LXR反应元件。LXR的激活剂量依赖性地抑制胰腺β细胞活力和增殖。这伴随着β细胞周期停滞在G1期。此外，LXR激活通过抑制其降解来增加p27蛋白的水平。敲低p27逆转这些影响LXR激活生长抑制和细胞周期arrest.Conclusions/interpretationOur观察表明，LXR激活抑制胰腺β细胞增殖通过细胞周期阻滞。众所周知的胰腺β细胞周期进程调节因子p27被上调并介导LXR对β细胞生长抑制的作用。这些观察结果表明LXR的异常激活参与β细胞质量不足，这是2型糖尿病发展的重要步骤。
Aims/hypothesisLiver X receptors (LXRs) are important transcriptional regulators of lipid homeostasis and proliferation in several cell types. However, the roles of LXRs in pancreatic beta cells have not been fully established. The aim of this study was to investigate the effects of LXRs on pancreatic beta cell proliferation.MethodsGene expression was analysed using real-time RT-PCR. Transient transfection and reporter gene assays were used to determine the transcriptional activity of LXRs in pancreatic beta cells. Cell viability and proliferation were analysed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), DNA fluorometric, BrdU labelling and [3H]thymidine incorporation assays. Cell cycle distribution was investigated by flow cytometry analysis. Adenovirus-based RNA interference was used to knockdown LXRα, LXRβ and p27 in MIN6 cells and mouse islets.ResultsWe found that bothLxrα(also known asNr1h3) andLxrβ(also known asNr1h2) were expressed and transactivated the LXR response element in HIT-T15 and MIN6 cells. Activation of LXRs dose-dependently inhibited pancreatic beta cell viability and proliferation. This was accompanied by beta cell cycle arrest at the G1 phase. Furthermore, LXR activation increased levels of the p27 protein by inhibiting its degradation. Knockdown of p27 reversed these effects of LXR activation on growth inhibition and cell cycle arrest.Conclusions/interpretationOur observations indicate that LXR activation inhibits pancreatic beta cell proliferation through cell cycle arrest. A well-known regulator of pancreatic beta cell cycle progression, p27, is upregulated and mediates the effects of LXRs on growth inhibition in beta cells. These observations suggest the involvement of aberrant activation of LXR in beta cell mass inadequacy, which is an important step in the development of type 2 diabetes.