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首页> 外文学位 >Small nucleolar RNAs U32a, U33, and U35a are critical mediators of liptoxic and oxidative stress.
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Small nucleolar RNAs U32a, U33, and U35a are critical mediators of liptoxic and oxidative stress.

机译：小核仁RNA U32a，U33和U35a是脂毒性和氧化应激的关键介质。

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摘要

Obesity and diabetes are characterized by elevated serum triglycerides, and free fatty acids, due to insulin resistance. In these diseases, the capacity for lipid storage in adipose tissue is exceeded, leading to delivery of fatty acid substrates to non-adipose tissues and resulting in lipid accumulation. Ectopic lipid accumulation is associated with cellular dysfunction and cell death through the process of lipotoxicity, and this metabolic stress response has been implicated to play a key role in the pathogenesis of complications of diabetes and obesity. Though a variety of stress responses have been shown to mediate lipotoxicity, the precise molecular players linking deleterious lipid-accumulation and cellular dysfunction are still largely unknown.;To elucidate the molecular mechanisms of lipotoxicity, we used retroviral promoter trap mutagenesis to isolate a Chinese hamster ovary (CHO) cell line that is resistant to lipotoxic and oxidative stress. Proviral insertion in this mutant renders it haploinsufficient for ribosomal protein L13a (rpL13a). We show that loss of three box C/D small nucleolar RNAs (snoRNAs) encoded in the rpL13a locus in CHO cells is sufficient to confer resistance to lipotoxic and oxidative stress. Complementation of this phenotype is dependant on the expression of snoRNAs U32a, U33, and U35a from the rpL13a genomic locus. Furthermore, we demonstrate that lipotoxic and oxidative stress induce U32a, U33, and U35a snoRNA expression, and targeted depletion of snoRNAs confers resistance to lipotoxic and oxidative stress induced cell death in murine cells. Our findings demonstrate a novel role for snoRNAs U32a, U33, and U35a as critical mediators of lipotoxic and oxidative stress.;Canonical snoRNAs can serve as guides for the modification of ribosomal RNA in the nucleolus. However, our results suggest that rpL13a encoded snoRNAs do not mediate lipotoxic stress through this mechanism. We hypothesize that snoRNAs U32a, U33, and U35a function through interaction with mRNA transcripts in order to regulate gene expression that activates cellular stress responses. In conclusion, our work demonstrates a previously unappreciated role for snoRNAs as regulators of metabolic stress response pathways in mammalian cells.
机译：肥胖和糖尿病的特征是由于胰岛素抵抗，血清甘油三酸酯和游离脂肪酸升高。在这些疾病中，脂质在脂肪组织中的储存能力被超过，导致脂肪酸底物向非脂肪组织的递送并导致脂质蓄积。异位脂质蓄积通过脂毒性过程与细胞功能障碍和细胞死亡有关，这种代谢应激反应被认为在糖尿病和肥胖症并发症的发病机理中起关键作用。尽管已显示出多种应激反应可介导脂毒性，但仍不清楚将有害的脂质积累与细胞功能障碍联系起来的确切分子机制。为了阐明脂毒性的分子机制，我们使用了逆转录病毒启动子诱集诱变技术来分离中国仓鼠。抗脂毒性和氧化应激的卵巢（CHO）细胞系。在该突变体中的原病毒插入使其对于核糖体蛋白L13a（rpL13a）的单倍不足。我们显示CHO细胞在rpL13a基因座中编码的三个框C / D小核仁RNA（snoRNAs）的丢失足以赋予对脂毒性和氧化应激的抗性。该表型的互补取决于来自rpL13a基因组位点的snoRNA U32a，U33和U35a的表达。此外，我们证明了脂毒性和氧化应激诱导U32a，U33和U35a snoRNA表达，并且snoRNA的靶向耗竭赋予了鼠类细胞对脂毒性和氧化应激诱导的细胞死亡的抗性。我们的发现证明snoRNA U32a，U33和U35a作为脂毒性和氧化应激的关键介体具有新作用。规范的snoRNA可以用作修饰核仁中核糖体RNA的指南。但是，我们的结果表明，rpL13a编码的snoRNAs不通过这种机制介导脂毒性应激。我们假设snoRNA U32a，U33和U35a通过与mRNA转录物相互作用来起作用，以调节激活细胞应激反应的基因表达。总之，我们的工作证明了snoRNA在哺乳动物细胞中作为代谢应激反应途径的调节剂的作用是前所未有的。

著录项

  • 作者

    Michel, Carlos Ivan.;

  • 作者单位

    Washington University in St. Louis.;

  • 授予单位 Washington University in St. Louis.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 137 p.
  • 总页数 137
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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