Atherton Helen J, Gulston Melanie K, Bailey Nigel J, Cheng Kian-Kai, Zhang Wen, Clarke Kieran, Griffin Julian L
Department of Biochemistry & Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK.
Mol Syst Biol. 2009;5:259. doi: 10.1038/msb.2009.18. Epub 2009 Apr 7.
Regulation between the fed and fasted states in mammals is partially controlled by peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Expression of the receptor is high in the liver, heart and skeletal muscle, but decreases with age. A combined (1)H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry metabolomic approach has been used to examine metabolism in the liver, heart, skeletal muscle and adipose tissue in PPAR-alpha-null mice and wild-type controls during ageing between 3 and 13 months. For the PPAR-alpha-null mouse, multivariate statistics highlighted hepatic steatosis, reductions in the concentrations of glucose and glycogen in both the liver and muscle tissue, and profound changes in lipid metabolism in each tissue, reflecting known expression targets of the PPAR-alpha receptor. Hepatic glycogen and glucose also decreased with age for both genotypes. These findings indicate the development of age-related hepatic steatosis in the PPAR-alpha-null mouse, with the normal metabolic changes associated with ageing exacerbating changes associated with genotype. Furthermore, the combined metabolomic and multivariate statistics approach provides a robust method for examining the interaction between age and genotype.
哺乳动物进食和禁食状态之间的调节部分受过氧化物酶体增殖物激活受体α（PPAR-α）控制。该受体在肝脏、心脏和骨骼肌中表达较高，但会随年龄增长而降低。采用联合的氢核磁共振（1H NMR）光谱法和气相色谱-质谱联用代谢组学方法，研究了3至13个月龄的PPAR-α基因敲除小鼠和野生型对照小鼠肝脏、心脏、骨骼肌及脂肪组织中的代谢情况。对于PPAR-α基因敲除小鼠，多变量统计分析突出显示了肝脂肪变性、肝脏和肌肉组织中葡萄糖和糖原浓度降低，以及每个组织中脂质代谢的显著变化，这反映了PPAR-α受体已知的表达靶点。两种基因型的肝脏糖原和葡萄糖也都随年龄增长而减少。这些发现表明PPAR-α基因敲除小鼠出现了与年龄相关的肝脂肪变性，与衰老相关的正常代谢变化加剧了与基因型相关的变化。此外，联合代谢组学和多变量统计方法为研究年龄与基因型之间的相互作用提供了一种可靠的方法。
