Regulation of genes encoding enzymes involved in carnitine biosynthesis by peroxisome proliferator-activated receptor of alpha (PPARalpha)

过氧化物酶体增殖物激活α受体（PPARα）对参与肉碱生物合成的编码酶基因的调节

• 批准号: 170378827
• 负责人: Professor Dr. Klaus Eder
• 金额: --
• 依托单位: Institut für Tierernährung & Ernährungsphysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/170378827?language=en
• 关键词: Regulation; genes; encoding; enzymes; involved

Recent studies strongly support the hypothesis that genes encoding enzymes involved incarnitine synthesis are directly regulated by peroxisome proliferator-activated receptor α(PPARα). PPARα is a ligand-activated transcription factor that acts as an important regulatorof lipid metabolism and energy homeostasis in mammals. Transcriptional regulation of genesby PPARα is mediated by binding of activated PPAR/retinoid X receptor heterodimers tospecific DNA sequences, called peroxisome proliferator response elements (PPRE) presentin and around the promoter of target genes. The presence of a functional PPRE within apromoter region has been accepted as the best criterion to classify a gene as a PPARαtarget gene. So far, functional PPRE have not yet been described for the promoters of genesencoding enzymes involved in carnitine biosynthesis such as trimethyllysine dioxygenase(TMLD), trimethylaminoaldehyde dehydrogenase (TMABA-DH) and γ-butyrobetainedioxygenase (γ-BBD). Therefore, the aim of this project is to explore the transcriptionalregulation of TMLD, TMABA-DH and BBD by PPARα. For this purpose, reporter gene assayswith wild-type and mutant TMLD, TMABA-DH and BBD promoter reporter truncationconstructs, electrophoretic mobility shift assays, and chromatin immuno-precipitation assayswill be performed. The investigations of the present project are original and will provide directproof whether genes encoding enzymes involved in carnitine synthesis are PPARα targetgenes with functional PPRE or not. Because PPARα has been mostly considered as a keyregulator of fatty acid catabolism and glucose homeostasis, the results of this project willshow whether PPARα also functions directly as an essential regulator of carnitine synthesis.

最近的研究强烈支持这样的假设：编码参与肉毒碱合成的酶的基因受过氧化物酶体增殖物激活受体 α (PPARα) 直接调节。 PPARα 是一种配体激活的转录因子，是哺乳动物脂质代谢和能量稳态的重要调节因子。 PPARα 对基因的转录调节是通过激活的 PPAR/类视黄醇 X 受体异二聚体与特定 DNA 序列（称为过氧化物酶体增殖物反应元件 (PPRE) 存在于靶基因启动子中和周围）的结合来介导的。启动子区域内功能性 PPRE 的存在已被接受为将基因分类为 PPARα 靶基因的最佳标准。迄今为止，尚未描述参与肉毒碱生物合成的基因编码酶的启动子的功能性PPRE，例如三甲基赖氨酸双加氧酶(TMLD)、三甲氨基醛脱氢酶(TMABA-DH)和γ-丁酰甜二加氧酶(γ-BBD)。因此，本项目的目的是探讨PPARα对TMLD、TMABA-DH和BBD的转录调控。为此，将使用野生型和突变型 TMLD、TMABA-DH 和 BBD 启动子报告基因截短构建体进行报告基因测定、电泳迁移率变动测定和染色质免疫沉淀测定。本项目的研究是原创的，将为肉碱合成酶的编码基因是否是具有功能性PPRE的PPARα靶基因提供直接证据。由于 PPARα 通常被认为是脂肪酸分解代谢和葡萄糖稳态的关键调节因子，因此该项目的结果将表明 PPARα 是否也直接作为肉碱合成的重要调节因子发挥作用。