Exposure to Stearate Activates the IRE1α/XBP-1 Pathway in 3T3-L1 Adipocytes.
Exposure to Stearate Activates the IRE1α/XBP-1 Pathway in 3T3-L1 Adipocytes.
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DOI：
10.1248/bpb.b21-00478
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发表时间：
2021-11
影响因子：
2
通讯作者：
Yoshihiro Takeda;K. Ishibashi;Yumi Kuroda;G. Atsumi
中科院分区：
文献类型：
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作者：
Yoshihiro Takeda;K. Ishibashi;Yumi Kuroda;G. Atsumi
在内质网（ER）中，具有畸形高级结构的异常蛋白质的积累激活信号通路（肌醇需要酶1α（IRE 1 α）/X-box结合蛋白1（XBP-1）途径，蛋白激酶RNA激活样内质网激酶（PERK）/CCAAT/增强子结合蛋白同源蛋白（CHOP）途径和转录激活因子6α（ATF 6 α）途径）导致细胞反应抑制异常蛋白质的产生或诱导细胞凋亡。这些反应统称为未折叠蛋白反应（UPR）。近年来，研究表明肝细胞和胰腺β细胞中饱和脂肪酸诱导的UPR参与了糖尿病等代谢性疾病的发生发展。棕榈酸酯（一种饱和脂肪酸）对UPR的影响也在脂肪细胞中进行了研究，这与代谢紊乱的发展有关，但结果不确定。因此，由于日常饮食中存在的主要饱和脂肪酸是棕榈酸酯和硬脂酸酯，我们研究了这些饱和脂肪酸对脂肪细胞中UPR的影响。在这里，我们表明，饱和脂肪酸引起有限的激活脂肪细胞中的UPR。暴露于硬脂酸盐几个小时会提高XBP-1 mRNA的剪接比例，并且这种作用比棕榈酸盐更强。此外，在暴露于硬脂酸盐的3 T3-L1脂肪细胞中，XBP-1上游的IRE 1 α的磷酸化水平及其下游靶点如DNAJB 9和Pdia 6的表达水平升高。另一方面，硬脂酸盐不影响PERK的磷酸化、其对CHOP的活化或ATF 6 α的裂解。因此，在脂肪细胞中，暴露于硬脂酸盐通过IRE 1 α/XBP-1途径激活UPR，而不是PERK/CHOP和ATF 6 α途径。
In the endoplasmic reticulum (ER), accumulation of abnormal proteins with malformed higher-order structures activates signaling pathways (inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway, protein kinase RNA-activated-like endoplasmic reticulum kinase (PERK)/CCAAT/enhancer binding protein-homologous protein (CHOP) pathway and activating transcription factor 6α (ATF6α) pathway) that result in a cellular response suppressing the production of abnormal proteins or inducing apoptosis. These responses are collectively known as the unfolded protein response (UPR). Recently, it has been suggested that the UPR induced by saturated fatty acids in hepatocytes and pancreatic β cells is involved in the development of metabolic diseases such as diabetes. The effect of palmitate, a saturated fatty acid, on the UPR has also been investigated in adipocytes, which are associated with the development of metabolic disorders, but the results were inconclusive. Therefore, as the major saturated fatty acids present in the daily diet are palmitate and stearate, we examined the effects of these saturated fatty acids on UPR in adipocytes. Here, we show that saturated fatty acids caused limited activation of the UPR in adipocytes. Exposure to stearate for several hours elevated the ratio of spliced XBP-1 mRNA, and this effect was stronger than that of palmitate. Moreover, the phosphorylation level of IRE1α, upstream of XBP-1 and expression levels of its downstream targets such as DNAJB9 and Pdia6 were elevated in 3T3-L1 adipocytes exposed to stearate. On the other hand, stearate did not affect the phosphorylation of PERK, its activation of CHOP, or the cleavage of ATF6α. Thus, in adipocytes, exposure to stearate activates the UPR via the IRE1α/XBP-1 pathway, but not the PERK/CHOP and ATF6α pathway.