在肝脏中鉴定了对PPARalpha具有生理学意义的内源性连接体
Manu V Chakravarthy1, Irfan J Lodhi, Li Yin
1Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Cell
|August 4, 2009
概括
脂肪酸合成酶 (FAS) 有助于产生脂,1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC),它作为核受体PPARalpha的内源性配体,影响脂质代谢.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 代谢疾病 代谢疾病
背景情况:
- 核受体PPARalpha是脂质代谢障碍的药物标.
- 对于PPARalpha的内源性连接体仍然未被确定.
- 脂肪酸合成酶 (FAS) 失活会损害PPARalpha依赖基因表达,这表明它在配体生成中的作用.
研究的目的:
- 为了识别PPARalpha的内源性连接体.
- 调查脂肪酸合成酶 (FAS) 在PPARalpha连接体生产中的作用.
- 描述已识别的配体与PPARalpha的相互作用及其对基因表达和肝脏肥胖症的影响.
主要方法:
- 从小鼠肝脏中分离并分析与PPARalpha结合的脂.
- 质谱测量用于识别结合的脂物种.
- 基因表达分析在酸胆合成酶的淘汰后进行 (Cept1).
- 在体外结合测定用PPARalpha,PPARdelta和PPARgamma.
- 在体内研究涉及对已识别的配体的门静脉输液.
主要成果:
- 一种脂,1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC),被确定与小鼠肝脏中的PPARalpha结合.
- FAS活性与16:0/18:1-GPC与PPARalpha结合的存在相关.
- Knockdown of Cept1,一种酸丁胆合成酶,减少了PPARalpha-依赖的基因表达.
- 16:0/18:1-GPC与PPARalpha表现出强烈的相互作用,与已知的激动剂相当.
- 输注16:0/18:1-GPC激活了PPARα-依赖基因表达,并减少了肝硬化症 in vivo.
结论:
- 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC) 是PPARalpha的一种生理上相关的内源性联体.
- 脂肪酸合成酶 (FAS) 和酸胆合成对于产生这种PPARalpha连接体至关重要.
- 这一发现为调节脂质代谢和针对PPARalpha的潜在治疗策略提供了新的见解.
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