Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting
Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting
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DOI：
10.1172/jci6223
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发表时间：
1999-06-01
影响因子：
15.9
通讯作者：
Wrahli, W
中科院分区：
文献类型：
--
作者：
Kersten, S;Seydoux, J;Wrahli, W
长期缺乏食物会引起哺乳动物新陈代谢的巨大变化，包括从脂肪组织中释放大量脂肪酸，然后在肝脏中氧化。过氧化物酶体增殖物激活受体 α (PPAR α) 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发挥作用，表明 PPAR α 可能参与禁食的转录反应。为了研究这种可能性，PPAR α缺失小鼠接受高脂肪饮食或禁食，并将它们的反应与野生型小鼠进行比较。长期喂食高脂肪饮食的 PPAR α 缺失小鼠的肝脏中出现大量脂质积累。在禁食 24 小时的 PPAR α 缺失小鼠中也发现了类似的表型，这些小鼠还表现出严重的低血糖、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受到显着抑制。结果表明，为了适应肝脏脂肪酸氧化增加的需求，野生型小鼠禁食期间会诱导 PPAR α mRNA。数据表明，PPARa 在禁食期间能量储存的管理中发挥着关键作用。通过调节基因表达，PPARα 刺激肝脏脂肪酸氧化，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 (PPAR alpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPAR alpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPAR alpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPAR alpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPAR alpha-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, PPAR alpha mRNA is induced during fasting in wildtype mice. The data indicate that PPARa plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPAR alpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.