Altered pre-lamin A processing is a common mechanism leading to lipodystrophy
Altered pre-lamin A processing is a common mechanism leading to lipodystrophy
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DOI：
10.1093/hmg/ddi158
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发表时间：
2005-06-01
影响因子：
3.5
通讯作者：
Lattanzi, G
中科院分区：
文献类型：
--
作者：
Capanni, C;Mattioli, E;Lattanzi, G
脂肪营养不良是一组异质性的人类疾病，其特征在于与胰岛素抵抗和脂质代谢改变相关的体脂肪的异常分布。遗传性脂肪营养不良的发病机制尚不清楚;在分子水平上，它们与核纤层蛋白A/C、过氧化物酶体增殖物激活受体（PPAR γ）和其他看似无关的蛋白质的突变有关。在这项研究中，我们研究了核纤层蛋白A/C加工的特点是脂肪营养不良的表型：邓尼根型家族性部分脂肪营养不良，下颌骨肢端发育不良和非典型沃纳综合征。我们发现核纤层蛋白A前体特异性地积聚在脂肪营养不良细胞中。前核纤层蛋白A位于核膜上，与脂肪细胞转录因子固醇调节元件结合蛋白1（SREBP 1）共定位。使用免疫共沉淀实验，我们获得了SREBP 1和前核纤层蛋白A之间的体内相互作用的第一个证明。在患者成纤维细胞以及通过法尼基化抑制剂被迫积累前核纤层蛋白A的对照成纤维细胞中检测到SREBP 1与核纤层蛋白A前体的结合。相反，SREBP 1在体内不与培养的成纤维细胞中的成熟核纤层蛋白A或C相互作用。为了深入了解前核纤层蛋白A在脂肪组织中积累的作用，我们抑制了3 T3-L1前脂肪细胞中的核纤层蛋白A前体加工。我们的研究结果表明，前核纤层蛋白A螯合SREBP 1在核边缘，从而减少池的活性SREBP 1，通常激活过氧化物酶体增殖物激活受体γ和导致损害前脂肪细胞分化。这种缺陷可以通过曲格列酮治疗来挽救，曲格列酮是一种已知的激活脂肪形成程序的PPAR γ配体。
Lipodystrophies are a heterogeneous group of human disorders characterized by the anomalous distribution of body fat associated with insulin resistance and altered lipid metabolism. The pathogenetic mechanism of inherited lipodystrophies is not yet clear; at the molecular level they have been linked to mutations of lamin A/C, peroxisome proliferator-activated receptor (PPAR gamma) and other seemingly unrelated proteins. In this study, we examined lamin A/C processing in three laminopathies characterized by lipodystrophic phenotypes: Dunnigan type familial partial lipodystrophy, mandibuloacral dysplasia and atypical Werner's syndrome. We found that the lamin A precursor was specifically accumulated in lipodystrophy cells. Pre-lamin A was located at the nuclear envelope and co-localized with the adipocyte transcription factor sterol regulatory element binding protein 1 (SREBP1). Using co-immunoprecipitation experiments, we obtained the first demonstration of an in vivo interaction between SREBP1 and pre-lamin A. Binding of SREBP1 to the lamin A precursor was detected in patient fibroblasts as well as in control fibroblasts forced to accumulate pre-lamin A by farnesylation inhibitors. In contrast, SREBP1 did not interact in vivo with mature lamin A or C in cultured fibroblasts. To gain insights into the effect of pre-lamin A accumulation in adipose tissue, we inhibited lamin A precursor processing in 3T3-L1 pre-adipocytes. Our results show that pre-lamin A sequesters SREBP1 at the nuclear rim, thus decreasing the pool of active SREBP1 that normally activates PPAR gamma and causing impairment of pre-adipocyte differentiation. This defect can be rescued by treatment with troglitazone, a known PPAR gamma ligand activating the adipogenic program.