Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate
Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate
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DOI：
10.1073/pnas.1016354108
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发表时间：
2011-04-19
影响因子：
11.1
通讯作者：
Moschetta, Antonio
中科院分区：
文献类型：
--
作者：
D'Errico, Ilenia;Salvatore, Lorena;Moschetta, Antonio
过氧化物酶体增殖物激活受体-γ共激活因子1-α(Pgc1α)是一种转录共激活剂，能够上调线粒体的生物发生、呼吸能力、氧化磷酸化和脂肪酸β氧化，最终目的是为有氧能量的产生提供一条更有效的途径。在不断更新的肠上皮中，隐窝内的增殖细胞沿绒毛轴迁移并分化为成熟的肠细胞，增加其呼吸量，最终发生凋亡。在这里，我们发现在肠上皮细胞表面，PGC1α在抗氧化酶活性降低的情况下驱动线粒体的生物发生和呼吸，从而决定了活性氧物种的积累，并促进了肠细胞走向凋亡的命运。结合人类细胞和小鼠肠癌模型中的功能获得和功能丧失的遗传方法，我们提出了一个有趣的场景，即PGC1α调节肠细胞的命运并防止肿瘤发生。
Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1 alpha) is a transcriptional coactivator able to up-regulate mitochondrial biogenesis, respiratory capacity, oxidative phosphorylation, and fatty acid beta-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1 alpha drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain-and loss-of-function genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGC1 alpha regulates enterocyte cell fate and protects against tumorigenesis.