Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells.
Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells.
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DOI：
10.1186/1476-511x-9-108
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发表时间：
2010-09-29
影响因子：
4.5
通讯作者：
Bergsten P
中科院分区：
文献类型：
--
作者：
Thörn K;Hovsepyan M;Bergsten P
硬脂酰辅酶A去饱和酶1(SCD1)是一种内质网驻留酶，在饱和脂肪酸中引入双键。在小鼠中，SCD1基因的全局敲除增加了脂肪酸氧化和胰岛素敏感性，使动物对饮食诱导的肥胖具有抵抗力。因此，抑制SCD1被认为是一种潜在的代谢综合征的治疗方法。然而，大部分工作都集中在胰岛素靶组织上，而关于Scd1水平降低会如何影响产生胰岛素的β细胞，人们知之甚少。因此，本研究的目的是研究Scd1水平降低对β细胞的影响。通过siRNA介导的基因敲除，建立了SCD1表达水平降低的胰岛素分泌MIN6细胞。当检测脂肪酸氧化时，SCD1表达水平降低的细胞与假转染组细胞之间没有差异。此外，降低SCD1水平不会影响对葡萄糖的胰岛素分泌。为了研究SCD1基因敲除是如何影响细胞机制的，用蛋白质组学的方法鉴定了差异调节蛋白。SCD1水平降低的细胞具有更高水平的ER伴侣和蛋白酶体成分。较高剂量并不能保护β细胞免受棕榈酸酯诱导的内质网应激和细胞凋亡的影响。相反，在棕榈酸酯暴露后，p-eif2scd1和CHOP水平的上升在α水平降低的细胞中是模拟转染组的两倍。相应地，在接触棕榈酸酯后，与模拟转染组相比，SCD1水平降低的细胞的凋亡率上升到更高的水平。总之，降低Scd1的水平会增加棕榈酸酯诱导的内质网应激和β细胞的凋亡，这是考虑将该酶作为治疗代谢综合征的靶点时的一个重要警告。
Stearoyl-CoA desaturase 1 (SCD1) is an ER resident enzyme introducing a double-bond in saturated fatty acids. Global knockout of SCD1 in mouse increases fatty acid oxidation and insulin sensitivity which makes the animal resistant to diet-induced obesity. Inhibition of SCD1 has therefore been proposed as a potential therapy of the metabolic syndrome. Much of the work has focused on insulin target tissue and very little is known about how reduced levels of SCD1 would affect the insulin-producing β-cell, however. The aim of the present study was therefore to investigate how reduced levels of SCD1 affect the β-cell. Insulin-secreting MIN6 cells with reduced levels of SCD1 were established by siRNA mediated knockdown. When fatty acid oxidation was measured, no difference between cells with reduced levels of SCD1 and mock-transfected cells were found. Also, reducing levels of SCD1 did not affect insulin secretion in response to glucose. To investigate how SCD1 knockdown affected cellular mechanisms, differentially regulated proteins were identified by a proteomic approach. Cells with reduced levels of SCD1 had higher levels of ER chaperones and components of the proteasome. The higher amounts did not protect the β-cell from palmitate-induced ER stress and apoptosis. Instead, rise in levels of p-eIF2α and CHOP after palmitate exposure was 2-fold higher in cells with reduced levels of SCD1 compared to mock-transfected cells. Accordingly, apoptosis rose to higher levels after exposure to palmitate in cells with reduced levels of SCD1 compared to mock-transfected cells. In conclusion, reduced levels of SCD1 augment palmitate-induced ER stress and apoptosis in the β-cell, which is an important caveat when considering targeting this enzyme as a treatment of the metabolic syndrome.