Palmitate Causes Endoplasmic Reticulum Stress and Apoptosis in Human Mesenchymal Stem Cells: Prevention by AMPK Activator
Palmitate Causes Endoplasmic Reticulum Stress and Apoptosis in Human Mesenchymal Stem Cells: Prevention by AMPK Activator
复制标题
棕榈酸酯导致人间充质干细胞内质网应激和细胞凋亡：AMPK 激活剂的预防。
DOI：
10.1210/en.2012-1418
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发表时间：
2012-11-01
期刊：
影响因子：
4.8
通讯作者：
Tan, Jianming
中科院分区：
文献类型：
--
作者：
Lu, Jun;Wang, Qinghua;Tan, Jianming
循环饱和脂肪酸浓度升高通常与糖尿病控制不良有关。普遍存在的游离脂肪酸棕榈酸酯可诱导多种细胞类型的凋亡，但对其对人间充质干细胞（MSCs）的影响知之甚少。在这里，我们报告了长期暴露于棕榈酸盐诱导人骨髓来源的MSC （hBM-MSC）和人脐带来源的MSC凋亡。我们研究了内质网（ER）应激的作用，这是已知的促进细胞凋亡。棕榈酸酯激活hBM-MSCs中XBP1剪接、elF2α（真核翻译起始因子2α）磷酸化以及CHOP、ATF4、BiP和GRP94转录。棕榈酸盐也能诱导hBM-MSCs中ERK1/2和p38 MAPK磷酸化。选择性p38抑制剂抑制棕榈酸酯对内质网应激的激活，而ERK1/2抑制剂没有作用。amp激活的蛋白激酶激活剂氨基咪唑羧酰胺核糖核苷酸阻断棕榈酸盐诱导的内质网应激和细胞凋亡。这些结果表明，棕榈酸盐可诱导内质网应激和hBM-MSCs中ERK1/2和p38的激活，而amp激活的蛋白激酶激活剂可通过抑制内质网应激和细胞凋亡来预防棕榈酸盐的有害作用。
Elevated circulating saturated fatty acids concentration is commonly associated with poorly controlled diabetes. The highly prevalent free fatty acid palmitate could induce apoptosis in various cell types, but little is known about its effects on human mesenchymal stem cells (MSCs). Here, we report that prolonged exposure to palmitate induces human bone marrow-derived MSC (hBM-MSC) and human umbilical cord-derived MSC apoptosis. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cell apoptosis. Palmitate activated XBP1 splicing, elF2α (eukaryotic translation initiation factor 2α) phosphorylation, and CHOP, ATF4, BiP, and GRP94 transcription in hBM-MSCs. ERK1/2 and p38 MAPK phosphorylation were also induced by palmitate in hBM-MSCs. A selective p38 inhibitor inhibited palmitate activation of the ER stress, whereas the ERK1/2 inhibitors had no effect. The AMP-activated protein kinase activator aminoimidazole carboxamide ribonucleotide blocked palmitate-induced ER stress and apoptosis. These findings suggest that palmitate induces ER stress and ERK1/2 and p38 activation in hBM-MSCs, and AMP-activated protein kinase activator prevents the deleterious effects of palmitate by inhibiting ER stress and apoptosis.