Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
Free Radic Biol Med. 2021 May 1;167:1-11. doi: 10.1016/j.freeradbiomed.2021.02.033. Epub 2021 Mar 8.
Rapamycin is a crucial immunosuppressive regimen for patients that have undergone liver transplantation (LT). However, one of the major side effects of rapamycin include metabolic disorders such as dyslipidemia, and the mechanism remains unknown. This study aims to explore the biomolecules that are responsible for rapamycin-induced dyslipidemia and the control strategies that can reverse the lipid metabolism disorder. In this study, data collected from LT patients, cell and mouse models treated with rapamycin were analyzed. Results showed an increase of triglycerides (TGs) induced by rapamycin. MicroRNAs (miRNAs) play important roles in many vital biological processes including TG metabolism. hsa-miR-372-3p was filtered using RNA sequencing and identified as a key regulator in rapamycin-induced TGs accumulation. Using bioinformatics and experimental analyses, target genes of hsa-miR-372-3p were predicted. These genes were alkylglycerone phosphate synthase (AGPS) and apolipoprotein C4 (APOC4), which are reported to be involved in TG metabolism. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was also identified as an upstream regulatory factor of hsa-miR-372-3p. From the results of this study, NEAT1/hsa-miR-372-3p/AGPS/APOC4 axis plays a vital role in rapamycin-disruption of lipid homeostasis. Therefore, targeting this axis is a potential therapeutic target combating rapamycin-induced dyslipidemia after LT.
雷帕霉素是肝移植（LT）患者的重要免疫抑制方案。然而，雷帕霉素的主要副作用之一包括代谢紊乱，如血脂异常，其机制尚不清楚。本研究旨在探讨导致雷帕霉素诱导血脂异常的生物分子以及可以逆转脂质代谢紊乱的控制策略。在这项研究中，分析了来自 LT 患者、用雷帕霉素处理的细胞和小鼠模型的数据。结果表明，雷帕霉素诱导甘油三酯（TGs）增加。微小 RNA（miRNA）在许多重要的生命过程中发挥重要作用，包括 TG 代谢。使用 RNA 测序筛选出 hsa-miR-372-3p，并将其鉴定为雷帕霉素诱导 TGs 积累的关键调节因子。通过生物信息学和实验分析，预测了 hsa-miR-372-3p 的靶基因。这些基因是烷基甘油磷酸合酶（AGPS）和载脂蛋白 C4（APOC4），它们被报道参与 TG 代谢。核斑蛋白组装转录物 1（NEAT1）也被鉴定为 hsa-miR-372-3p 的上游调节因子。从本研究结果来看，NEAT1/hsa-miR-372-3p/AGPS/APOC4 轴在雷帕霉素破坏脂质平衡中起着至关重要的作用。因此，针对该轴是治疗 LT 后雷帕霉素诱导血脂异常的潜在治疗靶点。
