Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 167, Issue -, Pages 1-11Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.02.033
Keywords
Liver transplantation; Rapamycin; microRNA; Dyslipidemia; Triglyceride metabolism
Funding
- National Natural Science Foundation of China [81930016, 81702858]
- Key Research & Development Plan of Zhejiang Province [2019C03050]
- National ST Major Project [2017ZX10203205]
- National Natural Science Funds for Distinguished Young Scholar of China [81625003]
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This study investigates the mechanism of rapamycin-induced dyslipidemia after liver transplantation by focusing on the role of microRNA hsa-miR-372?3p in regulating triglyceride metabolism through target genes AGPS and APOC4. The results suggest that the NEAT1/hsa-miR-372?3p/AGPS/APOC4 axis plays a crucial role in disrupting lipid homeostasis caused by rapamycin, providing a potential therapeutic target for combating dyslipidemia post-LT.
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 rapamycininduced 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 rapamycindisruption of lipid homeostasis. Therefore, targeting this axis is a potential therapeutic target combating rapamycin-induced dyslipidemia after LT.
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