12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response
12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response
复制标题
DOI：
10.1152/ajpendo.00373.2011
复制
发表时间：
2012-03-01
影响因子：
5.1
通讯作者：
Chakrabarti, Swarup K.
中科院分区：
文献类型：
--
作者：
Cole, Banumathi K.;Kuhn, Norine S.;Chakrabarti, Swarup K.
科尔BK，库恩NS，格林米切尔SM，利昂KA，Raab RM，Nadler JL，Chakrabarti SK。12/15-内质网应激反应中的脂氧合酶信号。Am J Physiol Endocrinol Metab 302：E654-E665，2012。首次发表于2012年1月3日; doi：10.1152/ajpendo.00373.2011.-向心性肥胖与慢性炎症、胰岛素抵抗、β细胞功能障碍和内质网（ER）应激有关。12/15-脂氧合酶（12/15-LO）促进脂肪和外周组织中的炎症和胰岛素抵抗。鉴于肥胖与ER应激相关，并且12/15-LO在脂肪组织中表达，我们确定12/15-LO是否可以介导ER应激信号。将12/15-LO脂质产物12（S）-HETE和12（S）-HPETE添加至分化的3 T3-L1脂肪细胞诱导ER应激标志物（包括BiP、XBP-1、p-PERK和p-IRE 1 α）的表达和活化。ER应激诱导剂衣霉素上调脂肪细胞中的ER应激标志物，伴随着12/15-LO活化。此外，12/15-LO抑制剂，CDC，衣霉素处理的脂肪细胞衰减ER应激反应。此外，12/15-LO缺陷的脂肪细胞表现出显着降低衣霉素诱导的ER应激。12/15-LO作用涉及白细胞介素-12（IL-12）表达的上调。衣霉素显著上调IL-12 p40在脂肪细胞中的表达，并且IL-12添加增加ER应激基因表达;相反，LSF（IL-12信号传导抑制剂）和IL-12 p40中和抗体减弱衣霉素诱导的ER应激。从喂食高脂饮食的12/15-LO缺陷小鼠分离的脂肪细胞和肝脏显示，与喂食高脂饮食的野生型C57 BL/6小鼠相比，剪接的XBP-1表达减少。此外，与野生型小鼠相比，来自12/15-LO缺陷小鼠的胰岛显示出减少的高脂饮食诱导的ER应激基因。这些数据表明，12/15-LO活性参与了脂肪细胞、胰岛和肝脏中的ER应激。因此，12/15-LO活性或表达的降低可以提供新的治疗靶点以减少与肥胖相关的ER应激和下游炎症。
Cole BK, Kuhn NS, Green-Mitchell SM, Leone KA, Raab RM, Nadler JL, Chakrabarti SK. 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response. Am J Physiol Endocrinol Metab 302: E654-E665, 2012. First published January 3, 2012; doi:10.1152/ajpendo.00373.2011.-Central obesity is associated with chronic inflammation, insulin resistance, beta-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1 alpha. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.