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首页> 外文学位 >Role of Sharp-1 during adipogenic differentiation, adipose tissue development and hepatic lipid metabolism.
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Role of Sharp-1 during adipogenic differentiation, adipose tissue development and hepatic lipid metabolism.

机译：Sharp-1在成脂分化，脂肪组织发育和肝脂质代谢中的作用。

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摘要

Sharp-1, a basic helix-loop-helix (bHLH) transcription factor is widely expressed in many tissues and plays roles in different cellular processes. However, the molecular mechanisms by which it regulates cellular differentiation remain largely unknown. In this study, we demonstrate that Sharp-1 inhibits adipogenic differentiation and its deficiency leads to an increase in serum insulin levels and liver triglyceride accumulation with high fat diet in mice with SV129/C57BL/6J genetic background. By overexpressing Sharp-1 in preadipocytes and using WT and Sharp-1 -/- mouse embryonic fibroblast (MEF) cells, we show that Sharp-1 inhibits adipogenic differentiation. While expression of the early adipogenic marker C/EBPbeta is not altered, its key downstream targets C/EBPalpha and PPARgamma are down-regulated by Sharp-1. Protein interaction analyses demonstrate that Sharp-1 interacts with C/EBPbeta and inhibits its transcriptional activity. In Sharp-1 overexpressing cells, the co-repressors histone deacetylase1 (HDAC1) and histone methyltransferase G9a are retained at the C/EBP regulatory sites in C/EBPalpha and PPARgamma2 promoters. Interestingly, troglitazone treatment results in displacement of HDAC1 and G9a and rescues the differentiation defect of Sharp-1 overexpressing cells. Our data indicate that Sharp-1 inhibits adipogenesis by regulating the capacity of C/EBPbeta to activate transcription by displacing co-repressors from the promoters of its transcriptional targets C/EBPalpha and PPARgamma2.;Increased adipose tissue mass and adipocyte size is observed in Sharp-1 -/- mice with SV129/C57BL/6J genetic background. Surprisingly, Sharp-1 deficiency would not lead to an increase in body weight with normal and HF diet but would lead elevated serum insulin, leptin levels and enhanced hepatic steatosis with HF diet. Moreover, enhanced hepatic steatosis in Sharp-1 -/- mice is associated with increased mRNA levels of hepatic free fatty acid (FFA) de novo synthesis genes and fatty acid transport genes. These results demonstrate that Sharp-1 plays roles in adipogenic differentiation by negatively regulating C/EBP transcriptional activity, and in obesity related hepatic steatosis via altering serum insulin levels and hepatic gene expression.
机译：Sharp-1，一种基本的螺旋-环-螺旋（bHLH）转录因子在许多组织中广泛表达，并在不同的细胞过程中发挥作用。但是，其调节细胞分化的分子机制仍然是未知的。在这项研究中，我们证明了在具有SV129 / C57BL / 6J遗传背景的小鼠中，高脂饮食会使Sharp-1抑制脂肪形成分化，并且其缺乏导致血清胰岛素水平和肝甘油三酸酯蓄积的增加。通过在前脂肪细胞中过表达Sharp-1并使用WT和Sharp-1-/-小鼠胚胎成纤维细胞（MEF），我们显示Sharp-1抑制脂肪形成。虽然早期成脂标记物C / EBPbeta的表达没有改变，但其关键的下游靶标C / EBPalpha和PPARgamma被Sharp-1下调。蛋白质相互作用分析表明Sharp-1与C / EBPbeta相互作用并抑制其转录活性。在Sharp-1过表达的细胞中，协同阻遏物组蛋白脱乙酰基酶1（HDAC1）和组蛋白甲基转移酶G9a保留在C / EBPalpha和PPARgamma2启动子的C / EBP调节位点。有趣的是，曲格列酮治疗可导致HDAC1和G9a置换并挽救Sharp-1过表达细胞的分化缺陷。我们的数据表明Sharp-1通过调节C / EBPbeta通过从其转录靶C / EBPalpha和PPARgamma2的启动子上置换共抑制子来激活转录的能力来抑制脂肪形成;在Sharp中观察到脂肪组织质量和脂肪细胞大小增加具有SV129 / C57BL / 6J遗传背景的-1-/-小鼠。令人惊讶的是，Sharp-1缺乏症在正常饮食和HF饮食下不会导致体重增加，但会导致HF饮食的血清胰岛素，瘦素水平升高和肝脂肪变性增加。此外，夏普1-/-小鼠肝脏脂肪变性的增强与肝脏游离脂肪酸（FFA）从头合成基因和脂肪酸转运基因的mRNA水平升高有关。这些结果表明，Sharp-1通过负调节C / EBP转录活性在脂肪形成分化中发挥作用，并通过改变血清胰岛素水平和肝基因表达在肥胖相关的肝脂肪变性中发挥作用。

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  • 作者

    Kockara, Neriman Tuba.;

  • 作者单位

    Mount Sinai School of Medicine of New York University.;

  • 授予单位 Mount Sinai School of Medicine of New York University.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 169 p.
  • 总页数 169
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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