mir-98-5p通过靶向肝细胞中的PPP1R15B调控糖异生和脂肪生成

IF 3.6 3区 生物学 Q3 CELL BIOLOGY Journal of Cell Communication and Signaling Pub Date : 2023-03-14 DOI:10.1007/s12079-023-00735-0
Rukshar Khan, Amit Kumar Verma, Malabika Datta
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摘要

一些报告表明,循环mirna在多种疾病中不受调控,并被用作疾病诊断和预后的标志物。在这里,我们发现在糖尿病循环中下调的miR-98-5p通过靶向PPP1R15B调节肝脏糖异生和脂肪生成。miR-98-5p过表达显著降低PPP1R15B在肝HepG2细胞中的转录物和蛋白水平,增加p-eIF2α的表达,而这些在其抑制剂存在下被阻止。糖尿病期间的两个主要肝脏标志,即肝脏脂质积累和葡萄糖输出,探讨了生理相关性。与scramble相比,miR-98-5p的过表达降低了糖异生和脂肪生成基因的转录水平,同时显著减少了HepG2细胞中肝脏葡萄糖产生和脂肪积累。使用PASTAA检测调节这些改变基因的常见转录因子,CREB成为最显著富集的转录因子。虽然miR-98-5p过表达并未改变CREB的转录物水平,但其蛋白水平发生了显著变化。虽然使用PPP1R15B siRNA检测到对糖异生和脂生基因表达的类似影响,但单独存在miR-98-5p抑制剂时观察到相反的效果。所有这些都表明,miR-98-5p通过靶向PPP1R15B调节肝脏脂肪变性和葡萄糖输出;糖尿病患者肝脏的特征性特征是它们的放松。对miR-98/PPP1R15B轴的治疗干预可能提供了一种针对糖尿病期间肝脏代谢异常的潜在策略。
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mir-98-5p regulates gluconeogenesis and lipogenesis by targeting PPP1R15B in hepatocytes

Several reports suggest that circulatory miRNAs are deregulated in diverse diseases and used as markers for disease diagnosis and prognosis. Here we show that miR-98-5p, that is down-regulated in the circulation during diabetes, regulates hepatic gluconeogenesis and lipogenesis by targeting PPP1R15B. miR-98-5p overexpression significantly decreased the transcript and protein levels of PPP1R15B in hepatic HepG2 cells and increased p-eIF2α expression and these were prevented in the presence of its inhibitor. Two major hepatic hallmarks during diabetes i.e. hepatic lipid accumulation and glucose output were explored towards physiological relevance. As compared to scramble, overexpression of miR-98-5p decreased the transcript levels of both gluconeogenic and lipogenic genes together with a significant reduction in hepatic glucose production and fat accumulation in HepG2 cells. Using PASTAA to detect common transcription factors regulating these altered genes, CREB emerged as the most significantly enriched transcription factor. While miR-98-5p overexpression did not change the transcript levels of CREB, there was a significant change in its protein levels. While similar effects on gluconeogenic and lipogenic gene expression were detected using the PPP1R15B siRNA, the opposite was observed in the presence of miR-98-5p inhibitor alone. All these suggest that by targeting PPP1R15B, miR-98-5p regulates hepatic steatosis and glucose output; deregulation of which are characteristic hepatic features during diabetes. Therapeutic intervention of the miR-98/PPP1R15B axis might offer a potential strategy to target aberrant hepatic metabolism during diabetes.

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来源期刊
CiteScore
6.40
自引率
4.90%
发文量
40
期刊介绍: The Journal of Cell Communication and Signaling provides a forum for fundamental and translational research. In particular, it publishes papers discussing intercellular and intracellular signaling pathways that are particularly important to understand how cells interact with each other and with the surrounding environment, and how cellular behavior contributes to pathological states. JCCS encourages the submission of research manuscripts, timely reviews and short commentaries discussing recent publications, key developments and controversies. Research manuscripts can be published under two different sections : In the Pathology and Translational Research Section (Section Editor Andrew Leask) , manuscripts report original research dealing with celllular aspects of normal and pathological signaling and communication, with a particular interest in translational research. In the Molecular Signaling Section (Section Editor Satoshi Kubota) manuscripts report original signaling research performed at molecular levels with a particular interest in the functions of intracellular and membrane components involved in cell signaling.
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