Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation -: A mechanism for hypoxia-dependent effect
Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation -: A mechanism for hypoxia-dependent effect
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DOI：
10.1074/jbc.m407258200
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发表时间：
2004-09-24
影响因子：
4.8
通讯作者：
Casteilla, L
中科院分区：
文献类型：
--
作者：
Carrière, A;Carmona, MC;Casteilla, L
最近的报告强调了线粒体在白色脂肪组织生物学中的重要性。除了在能量稳态中发挥重要作用外，线粒体还是活性氧生成的主要场所。当适度产生时，它们充当生理信号分子。因此，线粒体活性氧触发缺氧依赖性基因表达。因此，本研究测试了线粒体活性氧在脂肪细胞分化中的含义及其在这种分化的缺氧依赖性效应中的假定作用。线粒体活性氧产生的药理学操作证明线粒体活性氧的变化与3T3-F442A前脂肪细胞的脂肪细胞分化之间存在非常强的负相关性。此外，线粒体活性氧积极且特异性地控制脂肪形成阻遏物 CHOP-10/GADD153 的表达。缺氧 (1% O-2) 强烈增加活性氧的产生、缺氧诱导因子 1 和 CHOP-10/GADD153 的表达，并抑制脂肪细胞分化。所有这些缺氧依赖性效应都可以通过抗氧化剂部分预防。通过使用缺氧诱导因子 1α (HIF-1α) 缺陷的小鼠胚胎成纤维细胞，HIF-1α 被证明不是缺氧介导的 CHOP-10/GADD153 诱导所必需的。此外，比较缺氧和 CoCl2 对野生型或 HIF-1α 缺陷小鼠胚胎成纤维细胞脂肪细胞分化的影响表明，存在至少两条依赖或不依赖于 HIF-1α 存在的途径。总之，这些数据表明线粒体活性氧控制 CHOP-10/GADD153 表达，是抗脂肪形成信号分子，并触发脂肪细胞分化的缺氧依赖性抑制。
Recent reports emphasize the importance of mitochondria in white adipose tissue biology. In addition to their crucial role in energy homeostasis, mitochondria are the main site of reactive oxygen species generation. When moderately produced, they function as physiological signaling molecules. Thus, mitochondrial reactive oxygen species trigger hypoxia-dependent gene expression. Therefore the present study tested the implication of mitochondrial reactive oxygen species in adipocyte differentiation and their putative role in the hypoxia-dependent effect on this differentiation. Pharmacological manipulations of mitochondrial reactive oxygen species generation demonstrate a very strong and negative correlation between changes in mitochondrial reactive oxygen species and adipocyte differentiation of 3T3- F442A preadipocytes. Moreover, mitochondrial reactive oxygen species positively and specifically control expression of the adipogenic repressor CHOP-10/GADD153. Hypoxia (1% O-2) strongly increased reactive oxygen species generation, hypoxia-inducible factor-1 and CHOP-10/GADD153 expression, and inhibited adipocyte differentiation. All of these hypoxia-dependent effects were partly prevented by antioxidants. By using hypoxia-inducible factor-1alpha (HIF-1alpha)-deficient mouse embryonic fibroblasts, HIF-1alpha was shown not to be required for hypoxia-mediated CHOP-10/GADD153 induction. Moreover, the comparison of hypoxia and CoCl2 effects on adipocyte differentiation of wild type or HIF-1alpha deficient mouse embryonic fibroblasts suggests the existence of at least two pathways dependent or not on the presence of HIF-1alpha. Together, these data demonstrate that mitochondrial reactive oxygen species control CHOP-10/GADD153 expression, are antiadipogenic signaling molecules, and trigger hypoxia-dependent inhibition of adipocyte differentiation.