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首页> 外文学位 >The role of long-chain acyl-CoA synthetase Faa1p in fatty acid transport, activation and transcriptional regulation.
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The role of long-chain acyl-CoA synthetase Faa1p in fatty acid transport, activation and transcriptional regulation.

机译：长链酰基辅酶A合成酶Faa1p在脂肪酸运输，活化和转录调控中的作用。

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摘要

Long-chain fatty acids are complex, energy-rich compounds essential to all cells. We employ the lower eukaryotic Saccharomyces cerevisiae as a model to study fatty acid transport, activation, metabolism and gene regulation. We hypothesize ACSLs play pivotal roles in fatty acid trafficking and thus represent central players in the maintenance of intracellular lipid homeostasis. Disruption of FAA1 gene results in a deficiency in fatty acid transport and the downstream metabolism including fatty acid beta-oxidation and fatty acid-dependent gene transcription regulations. In addition to the well-characterized functions, we also noted yeast strains with deletions of FAA genes have reduced growth rates, are flocculent and have altered colony morphology. We observed reduced staining or vacuole fragmentation in faa1l, 4Delta and faal,2,3,4Delta cells using FM4-64 staining. We also observed increased free fatty acids but decreased phospholipids including PE, PI, PS and PC, and triglyceride synthesis in faa1,4Delta and faa1,2,3,4Delta strains. In a yeast two-hybrid library screen, we identified a specific interactor of Faa1p. Disruption of the YNM3 gene encoding Ynm3p resulted in increased fatty acid uptake, triglyceride and free fatty acids accumulation, and reduced expression of the fatty acid-responsive OLE1 gene. We propose that Ynm3p modulates fatty acid metabolism and gene regulation through attenuation of ACSL activities. We tested the role of Ynm3p in cell apoptosis and found that YB332 ynm3Delta strains had increased apoptosis. YB332 ynm3Delta also had strain-specific reduced growth rate, loss of the ability to grow in non-fermentable carbon source, and severely altered cellular morphology. Mammals express multiple isoforms of ACSLs (ACSL-1 and ACSL3-6) in various tissues. Four ACSLs from the rat were expressed in a yeast faa1,4Delta strain and their roles in fatty acid-dependent growth on cerulenin plate, fatty acid transport and trafficking were characterized. All four restored ACS activities yet varied in substrate preference. ACSL1, 4 and 6 were able to rescue fatty acid transport by vectorial acylation in a yeast faa1,4Delta strain. ACSL5 was unable to complement defects in fatty acid-dependent growth, transport and complex lipid synthesis in the yeast model system, consistent with its proposed role in mitochondrial lipid metabolism.
机译：长链脂肪酸是所有细胞必不可少的复杂，富含能量的化合物。我们采用较低的真核酿酒酵母作为模型来研究脂肪酸的运输，活化，代谢和基因调控。我们假设ACSLs在脂肪酸运输中起着关键作用，因此代表了维持细胞内脂质稳态的核心角色。 FAA1基因的破坏导致脂肪酸运输和下游代谢的缺乏，包括脂肪酸β-氧化和脂肪酸依赖性基因转录调控。除了功能明确的功能外，我们还注意到带有FAA基因缺失的酵母菌株的生长速率降低，絮凝并改变了菌落形态。我们观察到使用FM4-64染色在faa1、4Delta和faal，2、3、4Delta细胞中的染色减少或液泡碎片减少。我们还观察到在faa1,4Delta和faa1,2,3,4Delta菌株中游离脂肪酸增加，但磷脂减少，包括PE，PI，PS和PC，以及甘油三酸酯的合成。在酵母双杂交文库筛选中，我们确定了Faa1p的特定相互作用者。编码Ynm3p的YNM3基因的破坏导致脂肪酸摄取增加，甘油三酸酯和游离脂肪酸积聚，以及脂肪酸响应性OLE1基因的表达降低。我们建议Ynm3p通过减弱ACSL活动来调节脂肪酸代谢和基因调控。我们测试了Ynm3p在细胞凋亡中的作用，发现YB332 ynm3Delta菌株具有增加的细胞凋亡。 YB332 ynm3Delta还具有特定于菌株的生长速率降低，在不可发酵碳源中生长的能力丧失以及细胞形态严重改变的情况。哺乳动物在各种组织中表达多种ACSL（ACSL-1和ACSL3-6）同工型。在酵母faa1,4Delta菌株中表达了来自大鼠的4种ACSL，并表征了它们在铜绿素板上脂肪酸依赖性生长，脂肪酸运输和运输中的作用。所有四个恢复的ACS活性均在底物偏好方面有所不同。 ACSL1、4和6能够通过载体酰化作用在酵母faa1,4Delta菌株中拯救脂肪酸运输。 ACSL5无法弥补酵母模型系统中脂肪酸依赖性生长，转运和复杂脂质合成中的缺陷，与其在线粒体脂质代谢中的拟议作用一致。

著录项

  • 作者

    Tong, Fumin.;

  • 作者单位

    Albany Medical College of Union University.;

  • 授予单位 Albany Medical College of Union University.;
  • 学科 Health Sciences Nutrition.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 293 p.
  • 总页数 293
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;分子遗传学;
  • 关键词

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