Down-regulation of Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Expression Is Necessary for Adipocyte Differentiation
Down-regulation of Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Expression Is Necessary for Adipocyte Differentiation
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DOI：
10.1074/jbc.m109.078444
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发表时间：
2010-02-26
影响因子：
4.8
通讯作者：
Peiretti, Franck
中科院分区：
文献类型：
--
作者：
Bernot, Denis;Barruet, Emilie;Peiretti, Franck
基质金属蛋白酶活性对于脂肪组织形成过程中发生的适当细胞外基质重塑至关重要。四种基质金属蛋白酶（TIMP）组织抑制剂调节其活性。然而，TIMP在脂肪细胞分化中的作用知之甚少。我们发现，在脂肪细胞分化过程中，所有TIMP的表达都发生了变化，但TIMP-3的表达以其极端下调而著称。TIMP-3的表达与分化过程密切相关。事实上，它在脂肪细胞分化期间保持低水平，但当细胞分化被阻止时增加。我们确定了转录因子Sp1负责脂肪细胞分化过程中TIMP-3表达的调节。TIMP-3的过表达减少脂肪细胞分化，强调其在此过程中的积极作用。TIMP-3过表达降低了脂肪形成Kruppel样因子4（Klf 4）、早期生长反应2（Egr 2/Krox 20）和CAAT/增强子结合蛋白β（C/EBP β）的早期和专性关键诱导物的表达。我们的研究结果表明，在前脂肪细胞分化过程中，Sp1依赖性TIMP-3表达的减少是成功实施脂肪细胞分化程序所必需的。
Matrix metalloproteinase activity is essential for proper extracellular matrix remodeling that takes place during adipose tissue formation. Four tissue inhibitors of matrix metalloproteinases (TIMPs) regulate their activity. However, the role of TIMPs in adipocyte differentiation is poorly understood. We found that the expression of all TIMPs was modified during adipocyte differentiation, but that of TIMP-3 was distinguished by its extreme down-regulation. TIMP-3 expression was closely linked to the differentiation process. Indeed, it remained low during the adipocyte differentiation but increased when cell differentiation was prevented. We identified the transcription factor Sp1 as being responsible for the regulation of TIMP-3 expression during adipocyte differentiation. Overexpression of TIMP-3 reduced adipocyte differentiation, underlining its active role in this process. TIMP-3 overexpression decreased the expression of the early and obligate key inductors of adipogenesis Kruppel-like factor 4 (Klf4), early growth response 2 (Egr2/Krox20), and CAAT/enhancer-binding protein beta (C/EBP beta). Our results indicate that during preadipocyte differentiation, the Sp1-dependent decrease in TIMP-3 expression is required for the successful implementation of the adipocyte differentiation program.