The Human Lipodystrophy Gene Product Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Plays a Key Role in Adipocyte Differentiation
The Human Lipodystrophy Gene Product Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Plays a Key Role in Adipocyte Differentiation
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DOI：
10.1210/en.2009-0236
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发表时间：
2009-10-01
期刊：
影响因子：
4.8
通讯作者：
Chan, Lawrence
中科院分区：
文献类型：
--
作者：
Chen, Weiqin;Yechoor, Vijay K.;Chan, Lawrence
Berardinelli-Seip先天性脂肪营养不良2型基因（BSCL 2）的突变是先天性全身性脂肪营养不良2型患者的潜在缺陷。BSCL 2编码一种称为seipin的蛋白质，其功能在很大程度上尚不清楚。在这项研究中，我们研究了Bscl 2在调节脂肪细胞分化中的作用。Bscl 2 mRNA在体外3 T3-L1细胞中在标准脂肪酸诱导的脂肪形成过程中高度上调。然而，这种上调并不发生在间充质干细胞（C3 H10 T1/2细胞）的承诺，前脂肪细胞谱系。在C3 H10 T1/2细胞中通过短发夹RNA敲低Bscl 2对骨形态发生蛋白-4诱导的前脂肪细胞定型没有影响。然而，在3 T3-L1细胞中的敲低阻止了由标准激素鸡尾酒诱导的脂肪形成，但脂肪形成可以通过在分化的早期阶段添加过氧化物酶体增殖物激活受体-γ激动剂吡格列酮来挽救。有趣的是，在不存在标准激素的情况下，吡格列酮诱导的分化与上调的Bscl 2表达无关。另一方面，短发夹RNA敲低Bscl 2在很大程度上阻断吡格列酮诱导的脂肪分化。这些实验表明，Bscl 2可能是正常的脂肪形成所必需的;它的工作上游或在过氧化物酶体增殖物激活受体-γ的水平，使后者能够发挥其全部活性在脂肪形成。因此，Bscl 2功能的丧失干扰脂肪细胞分化期间脂肪形成的正常转录级联，导致脂肪几乎完全丧失或脂肪营养不良。（内分泌学150：4552-4561，2009）
Mutations in the Berardinelli-Seip congenital lipodystrophy 2 gene (BSCL2) are the underlying defect in patients with congenital generalized lipodystrophy type 2. BSCL2 encodes a protein called seipin, whose function is largely unknown. In this study, we investigated the role of Bscl2 in the regulation of adipocyte differentiation. Bscl2 mRNA is highly up-regulated during standard hormone-induced adipogenesis in 3T3-L1 cells in vitro. However, this up-regulation does not occur during mesenchymal stem cell (C3H10T1/2 cells) commitment to the preadipocyte lineage. Knockdown of Bscl2 by short hairpin RNA in C3H10T1/2 cells has no effect on bone morphogenetic protein-4-induced preadipocyte commitment. However, knockdown in 3T3-L1 cells prevents adipogenesis induced by a standard hormone cocktail, but adipogenesis can be rescued by the addition of peroxisome proliferator-activated receptor-gamma agonist pioglitazone at an early stage of differentiation. Interestingly, pioglitazone-induced differentiation in the absence of standard hormone is not associated with up-regulated Bscl2 expression. On the other hand, short hairpin RNA-knockdown of Bscl2 largely blocks pioglitazone-induced adipose differentiation. These experiments suggest that Bscl2 may be essential for normal adipogenesis; it works upstream or at the level of peroxisome proliferator-activated receptor-gamma, enabling the latter to exert its full activity during adipogenesis. Loss of Bscl2 function thus interferes with the normal transcriptional cascade of adipogenesis during fat cell differentiation, resulting in near total loss of fat or lipodystrophy. (Endocrinology 150: 4552-4561, 2009)