The circFASN/miR-33a pathway participates in tacrolimus-induced dysregulation of hepatic triglyceride homeostasis.,Signal Transduction and Targeted Therapy

当前位置： X-MOL 学术 › Signal Transduct. Target Ther. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

The circFASN/miR-33a pathway participates in tacrolimus-induced dysregulation of hepatic triglyceride homeostasis.
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2020-03-27 , DOI: 10.1038/s41392-020-0105-2
Chenzhi Zhang _{1,

2} , Kangchen Chen _{1,

2} , Rongli Wei _{1,

2} , Guanghan Fan _{1,

2} , Xuechun Cai _{1,

2} , Li Xu _{1,

2} , Beini Cen ₂ , Jianguo Wang _{1,

2} , Haiyang Xie ₂ , Shusen Zheng _{1,

2,

3} , Xiao Xu _{1,

2}

Affiliation

Dyslipidemia exhibits a high incidence after liver transplantation, in which tacrolimus, a widely used immunosuppressant, plays a fundamental role. MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism. However, their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear. In this study, we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins (SREBPs) and miR-33a. Our in silico and experimental analyses identified miR-33a as a direct target of circFASN. Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro. Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation. Clinically, the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a (46.3% vs. 18.8% p = 0.012, n = 73). Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis. MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia, providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.

中文翻译：

circFASN/miR-33a 通路参与他克莫司诱导的肝脏甘油三酯稳态失调。

肝移植后血脂异常的发生率很高，其中他克莫司作为一种广泛使用的免疫抑制剂，起着重要的作用。MicroRNAs 和相关的 circRNAs 代表了一类非编码 RNAs，它们被认为是与脂质代谢相关的基因的重要调节因子。然而，它们在他克莫司相关血脂异常中的转录活性和功能机制尚不清楚。在这项研究中，我们观察到他克莫司可以通过刺激甾醇反应元件结合蛋白 (SREBPs) 和 miR-33a 来诱导肝细胞中甘油三酯的积累。我们的计算机和实验分析将 miR-33a 确定为 circFASN 的直接目标。他克莫司可以下调 circFASN 并导致体内和体外 miR-33a 升高。circFASN的过表达或miR-33a的沉默降低了他克莫司对甘油三酯积累的促进作用。临床上，肝移植后血清 miR-33a 升高的肝移植受者血脂异常发生率高于血清 miR-33a 未升高的患者（46.3% vs. 18.8% p = 0.012，n = 73）。我们的结果表明，circFASN/miR-33a 调节系统在他克莫司诱导的脂质稳态破坏中发挥着独特的作用。MiR-33a 可能是他克莫司相关血脂异常的危险因素，为对抗肝移植后他克莫司引起的血脂异常提供了潜在的治疗靶点。肝移植后血清miR-33a升高的肝移植受者血脂异常发生率高于血清miR-33a未升高的患者（46.3% vs. 18.8% p = 0.012, n = 73）。我们的结果表明，circFASN/miR-33a 调节系统在他克莫司诱导的脂质稳态破坏中发挥着独特的作用。MiR-33a 可能是他克莫司相关血脂异常的危险因素，为对抗肝移植后他克莫司引起的血脂异常提供了潜在的治疗靶点。肝移植后血清miR-33a升高的肝移植受者血脂异常发生率高于血清miR-33a未升高的患者（46.3% vs. 18.8% p = 0.012, n = 73）。我们的结果表明，circFASN/miR-33a 调节系统在他克莫司诱导的脂质稳态破坏中发挥着独特的作用。MiR-33a 可能是他克莫司相关血脂异常的危险因素，为对抗肝移植后他克莫司引起的血脂异常提供了潜在的治疗靶点。

更新日期：2020-03-27

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文