LNK deficiency aggravates palmitate-induced preadipocyte apoptosis
LNK deficiency aggravates palmitate-induced preadipocyte apoptosis
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LNK 缺乏加剧棕榈酸酯诱导的前脂肪细胞凋亡
DOI：
10.1016/j.bbrc.2017.05.057
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发表时间：
2017-08-19
影响因子：
3.1
通讯作者：
Wang, Guan-lei
中科院分区：
文献类型：
--
作者：
Du, Jie-yi;Jin, Chen-chen;Wang, Guan-lei
LNK （SH2B3）是一种细胞内接头蛋白，负向调节造血干细胞和其他祖细胞的细胞增殖或自我更新。LNK也被认为是几个组织和器官中胰岛素抵抗和炎症反应的关键调节因子。LNK在脂肪组织中的功能尚不清楚。我们之前证实，2型糖尿病（T2DM）小鼠模型血清游离脂肪酸（FFAs）水平升高，内脏脂肪组织前脂肪细胞凋亡增加，表明存在脂肪毒性。本研究中，与对照组小鼠相比，高糖/脂肪饮食、低剂量链脲佐菌素诱导的T2DM小鼠模型中附睾脂肪组织中LNK的蛋白表达降低。因此，我们在体外3T3-L1前脂肪细胞凋亡模型中研究LNK是否可以调节棕榈酸盐诱导的前脂肪细胞凋亡。LNK特异性siRNA加剧了棕榈酸盐诱导的细胞凋亡，增加了caspase-3、Bax和细胞色素C的促凋亡蛋白水平；LNK cDNA过表达具有明显的抗凋亡作用。与此一致的是，LNK特异性siRNA进一步降低了棕榈酸盐降低的Akt Ser-473磷酸化，该磷酸化位于Bax和细胞色素c的上游。siRNA介导的LNK敲低加剧了棕榈酸盐诱导的线粒体膜去极化和线粒体源性活性氧的产生，而LNK过表达则减弱了这一作用。这些结果表明LNK在棕榈酸盐相关的前脂肪细胞凋亡中起调节作用，并可能参与脂肪组织功能障碍。(C) 2017年Elsevier Inc.出版。
LNK (SH2B3) is an intracellular adaptor protein that negatively regulates cellular proliferation or self renewal of hematopoietic stem cells and some other progenitor cells. LNK is also recognized as a key regulator of insulin resistance and inflammatory responses in several tissues and organs. The function of LNK in adipose tissue is unknown. We previously demonstrated that type 2 diabetes mellitus (T2DM) mouse model had elevated serum free fatty acids (FFAs) levels and increased preadipocyte apoptosis in visceral fat tissue, showing the occurrence of lipotoxicity. Herein, when compared to control mice, the protein expression of LNK decreased in epididymal fat tissue from the high-sucrose/fat diet, low-dose streptozotocin induced T2DM mouse model. We thus investigated whether LNK could regulate palmitate-induced preadipocyte apoptosis in an in vitro apoptotic model in 3T3-L1 preadipocytes. LNK specific siRNA exacerbated palmitate-induced apoptosis and increased pro-apoptotic protein levels of cleaved caspase-3, Bax and cytochrome C; while overexpression of LNK cDNA exhibited significant antiapoptotic effects. Consistently, LNK specific siRNA further decreased the Akt Ser-473 phosphorylation reduced by palmitate and located on upstream of Bax and cytochrome C. The siRNA-mediated LNK knockdown exacerbated mitochondrial membrane depolarization and mitochondrial-derived reactive oxygen species production induced by palmitate, whereas overexpression of LNK attenuated that. These results indicated that LNK plays a regulatory role in the palmitate-related preadipocyte apoptosis and might be involved in adipose tissue dysfunction. (C) 2017 Published by Elsevier Inc.