Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.
Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.
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发表时间：
1999
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通讯作者：
S. Kersten;J. Seydoux;J. Peters;F. Gonzalez;B. Desvergne;W. Wahli
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作者：
S. Kersten;J. Seydoux;J. Peters;F. Gonzalez;B. Desvergne;W. Wahli
长期缺乏食物会导致哺乳动物新陈代谢发生巨大变化，包括从脂肪组织释放大量脂肪酸，然后在肝脏中氧化。被称为过氧化物酶体增殖物激活受体α（PPARalpha）的核受体被发现在调节线粒体和过氧化物酶体脂肪酸氧化中起作用，这表明PPARalpha可能参与对禁食的转录反应。为了研究这种可能性，将PPARalpha缺失的小鼠进行高脂肪饮食或禁食，并将它们的反应与野生型小鼠的反应进行比较。长期喂食高脂肪饮食的PPARalpha-无效小鼠显示出肝脏中大量脂质积累。在禁食24小时的PPARalpha缺失小鼠中观察到类似的表型，这些小鼠也显示出严重的低血糖、低酮血症、体温过低和血浆游离脂肪酸水平升高，表明脂肪酸摄取和氧化的显著抑制。结果表明，为了适应肝脂肪酸氧化的需求增加，在野生型小鼠禁食期间诱导PPARalpha mRNA。数据表明，PPARalpha在禁食期间能量储存的管理中起着关键作用。通过调节基因表达，PPARalpha刺激肝脂肪酸氧化以提供可被其他组织代谢的底物。
Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.