Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids IMPLICATIONS IN RENAL TUBULAR INJURY INDUCED IN OBESITY AND DIABETES
Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids IMPLICATIONS IN RENAL TUBULAR INJURY INDUCED IN OBESITY AND DIABETES
复制标题
DOI：
10.1074/jbc.m115.698191
复制
发表时间：
2016-01-15
影响因子：
4.8
通讯作者：
Kanwar, Yashpal S.
中科院分区：
文献类型：
--
作者：
Tominaga, Tatsuya;Dutta, Rajesh K.;Kanwar, Yashpal S.
肾脏是各种代谢疾病的靶器官之一，包括糖尿病、代谢综合征和肥胖症。大多数代谢研究强调肾小球病理学，虽然肾小管间质室一直强调不足。这项研究突出了关于肾小管损伤的病理生物学的背景下，肌醇加氧酶（Miox），一种肾小管酶的机制。高脂饮食（HFD）小鼠肾脏的Miox表达和活性增加，后者与丝氨酸/苏氨酸残基的磷酸化有关。此外，固醇调节元件结合蛋白1（Srebp 1）和细胞/核损伤标志物的表达增加沿着凋亡加重和肾小管刷状缘丢失。在用棕榈酸酯/BSA处理的细胞中观察到类似的结果。在miox启动子中发现了多个甾醇响应元件和E-box基序，并且其活性受到棕榈酸/BSA的调节。电泳迁移率和ChIP测定证实了Srebp与miox启动子的共有序列的结合。棕榈酸酯/BSA处理的细胞暴露于雷帕霉素使Miox表达正常化并防止Srebp1核转位。此外，雷帕霉素处理减少了p53表达和凋亡。与雷帕霉素一样，srebp siRNA减少Miox表达。Miox的表达增加与喂食HFD的小鼠肾小管中活性氧（ROS）的产生和暴露于棕榈酸酯/BSA的细胞相关。miox和srebp1 siRNA都减少了ROS的产生。总的来说，这些发现表明，HFD或脂肪酸调节Miox表达/活性的转录、翻译和翻译后调节，并强调Miox是转录因子Srebp1的新靶点。可以想象，mTORC1/Srebp1/Miox通路的激活导致ROS的产生，最终导致肥胖状态下的肾小管间质损伤。
The kidney is one of the target organs for various metabolic diseases, including diabetes, metabolic syndrome, and obesity. Most of the metabolic studies underscore glomerular pathobiology, although the tubulo-interstitial compartment has been underemphasized. This study highlights mechanisms concerning the pathobiology of tubular injury in the context of myoinositol oxygenase (Miox), a tubular enzyme. The kidneys of mice fed a high fat diet (HFD) had increased Miox expression and activity, and the latter was related to phosphorylation of serine/threonine residues. Also, expression of sterol regulatory element-binding protein1 (Srebp1) and markers of cellular/nuclear damage was increased along with accentuated apoptosis and loss of tubular brush border. Similar results were observed in cells treated with palmitate/BSA. Multiple sterol-response elements and E-box motifs were found in the miox promoter, and its activity was modulated by palmitate/BSA. Electrophoretic mobility and ChIP assays confirmed binding of Srebp to consensus sequences of the miox promoter. Exposure of palmitate/ BSA-treated cells to rapamycin normalized Miox expression and prevented Srebp1 nuclear translocation. In addition, rapamycin treatment reduced p53 expression and apoptosis. Like rapamycin, srebp siRNA reduced Miox expression. Increased expression of Miox was associated with the generation of reactive oxygen species (ROS) in kidney tubules of mice fed an HFD and cell exposed to palmitate/BSA. Both miox and srebp1 siRNAs reduced generation of ROS. Collectively, these findings suggest that HFD or fatty acids modulate transcriptional, translational, and post-translational regulation of Miox expression/activity and underscore Miox being a novel target of the transcription factor Srebp1. Conceivably, activation of the mTORC1/Srebp1/Miox pathway leads to the generation of ROS culminating into tubulo-interstitial injury in states of obesity.