Sp1 Transcription Factor Interaction with Accumulated Prelamin A Impairs Adipose Lineage Differentiation in Human Mesenchymal Stem Cells: Essential Role of Sp1 in the Integrity of Lipid Vesicles
Sp1 Transcription Factor Interaction with Accumulated Prelamin A Impairs Adipose Lineage Differentiation in Human Mesenchymal Stem Cells: Essential Role of Sp1 in the Integrity of Lipid Vesicles
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DOI：
10.5966/sctm.2011-0010
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发表时间：
2012-04
影响因子：
6
通讯作者：
G. Ruiz de Eguino;A. Infante;K. Schlangen;A. Aransay;A. Fullaondo;Mario Soriano;J. García-Verdugo;Angel G. Martín;C. I. Rodríguez
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文献类型：
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作者：
G. Ruiz de Eguino;A. Infante;K. Schlangen;A. Aransay;A. Fullaondo;Mario Soriano;J. García-Verdugo;Angel G. Martín;C. I. Rodríguez
核纤层蛋白A（LMNA）相关的脂肪营养不良可能是遗传性的（与LMNA突变相关）或获得性的（与使用人类免疫缺陷病毒蛋白酶抑制剂[PI]相关），在这两种情况下，它们都具有共同的临床特征，如体脂分布异常或脂肪组织的普遍损失，代谢改变和早期心血管并发症。两种LMNA连锁脂肪营养不良的特征均为核纤层蛋白A前体核纤层蛋白A的蓄积。前层蛋白A积累诱导脂肪营养不良相关表型的病理机制仍不清楚。由于这些疾病中受影响的组织是间充质来源的，因此我们使用PI处理的人间充质干细胞生成了LMNA相关实验模型，其重现了在患者活检中观察到的表型。该模型已被证明是解开LMNA连锁脂肪营养不良的病理机制的有用工具，为鉴定潜在靶点以产生用于药物发现筛选的新疗法提供了理想的系统。我们报告的第一次，受损的脂肪形成是一个结果之间的相互作用积累的前层蛋白A和Sp1转录因子，隔离，从而导致细胞外基质基因表达的改变。事实上，我们的研究显示了Sp1在人间充质干细胞脂肪谱系分化中的一种新的、必要的和精细调节的作用。这些发现定义了一种新的生理实验模型来阐明LMNA相关的脂肪营养不良的病理机制，不仅为LMNA相关的脂肪营养不良的研究和治疗创造了新的机会，而且也为其他脂肪生成相关的代谢疾病创造了新的机会。
Lamin A (LMNA)‐linked lipodystrophies may be either genetic (associated with LMNA mutations) or acquired (associated with the use of human immunodeficiency virus protease inhibitors [PIs]), and in both cases they share clinical features such as anomalous distribution of body fat or generalized loss of adipose tissue, metabolic alterations, and early cardiovascular complications. Both LMNA‐linked lipodystrophies are characterized by the accumulation of the lamin A precursor prelamin A. The pathological mechanism by which prelamin A accumulation induces the lipodystrophy associated phenotypes remains unclear. Since the affected tissues in these disorders are of mesenchymal origin, we have generated an LMNA‐linked experimental model using human mesenchymal stem cells treated with a PI, which recapitulates the phenotypes observed in patient biopsies. This model has been demonstrated to be a useful tool to unravel the pathological mechanism of the LMNA‐linked lipodystrophies, providing an ideal system to identify potential targets to generate new therapies for drug discovery screening. We report for the first time that impaired adipogenesis is a consequence of the interaction between accumulated prelamin A and Sp1 transcription factor, sequestration of which results in altered extracellular matrix gene expression. In fact, our study shows a novel, essential, and finely tuned role for Sp1 in adipose lineage differentiation in human mesenchymal stem cells. These findings define a new physiological experimental model to elucidate the pathological mechanisms LMNA‐linked lipodystrophies, creating new opportunities for research and treatment not only of LMNA‐linked lipodystrophies but also of other adipogenesis‐associated metabolic diseases.