Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis
Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis
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DOI：
10.1074/jbc.m503885200
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发表时间：
2005-09-23
影响因子：
4.8
通讯作者：
Reue, K
中科院分区：
文献类型：
--
作者：
Péterfy, M;Phan, J;Reue, K
我们最近发现Lpin 1（lipin）基因突变是脂肪肝营养不良（fld）小鼠品系脂肪营养不良的原因。以往的研究表明，脂蛋白在脂肪形成中起关键作用，解释了fld小鼠脂肪缺乏的表型。在目前的研究中，我们证明，选择性mRNA剪接产生两种脂蛋白亚型，脂蛋白-α和脂蛋白-β，这是差异表达在脂肪细胞分化。Lipin-alpha表达在3 T3-L1细胞分化的第2天达到峰值，之后其水平逐渐降低。相比之下，脂蛋白-β表达在10小时时短暂升高，随后在20小时时下降至背景水平，并且在分化的第2天和第6天之间逐渐增加。两种脂蛋白亚型在亚细胞定位上也表现出差异。脂蛋白-α主要位于细胞核中，而脂蛋白-β主要位于3 T3-L1脂肪细胞的细胞质中，表明不同的细胞功能。使用表达lipin-α或lipin-α的原代小鼠胚胎成纤维细胞，我们证明了两种亚型之间的功能差异。而lipin-beta表达的作用是诱导脂肪生成基因。在体内，脂蛋白-β在成熟脂肪细胞中特异性过表达导致脂肪生成基因表达升高和脂肪细胞肥大，证实了脂蛋白-β在脂肪生成调节中的作用。总之，我们的数据表明，这两种脂质异构体在脂肪生成中具有不同但互补的功能，其中lipin-α在分化中起主要作用，lipin-β主要参与脂肪生成。
We recently identified mutations in the Lpin1 ( lipin) gene to be responsible for lipodystrophy in the fatty liver dystrophy (fld) mouse strain. Previous studies revealed that lipin plays a critical role in adipogenesis, explaining the adipose-deficient phenotype of the fld mouse. In the current study, we demonstrate that alternative mRNA splicing generates two lipin isoforms, lipin-alpha and lipin-beta, which are differentially expressed during adipocyte differentiation. Lipin-alpha expression peaks at day 2 of 3T3-L1 cell differentiation, after which its levels gradually decrease. In contrast, lipin-beta expression is transiently elevated at 10 h, followed by a drop to background levels at 20 h and a gradual increase between days 2 and 6 of differentiation. The two lipin isoforms also exhibit differences in subcellular localization. Lipin-alpha is predominantly nuclear, whereas lipin-beta is primarily located in the cytoplasm of 3T3-L1 adipocytes, suggesting distinct cellular functions. Using primary mouse embryonic fibroblasts expressing either lipin-alpha or lipin-alpha, we demonstrate functional differences between the two isoforms. Whereas effect of lipin-beta expression is the induction of lipogenic genes. In vivo, overexpression of lipin-beta specifically in mature adipocytes leads to elevated expression of lipogenic genes and adipocyte hypertrophy, confirming a role of lipin-beta in the regulation of lipogenesis. In conclusion, our data suggest that the two lipin isoforms have distinct, but complementary, functions in adipogenesis, with lipin-alpha playing a primary role in differentiation and lipin-beta being predominantly involved in lipogenesis.