MicroRNA-101 Inhibits Autophagy to Alleviate Liver Ischemia/reperfusion Injury Via Regulating the MTOR Signaling Pathway

Overview

Journal Int J Mol Med

Specialty Genetics

Date 2019 Feb 13

PMID 30747215

Citations 10

Authors

Hu Song

Chenyang Du

Xingxing Wang

Jianjun Zhang

Zhongyang Shen

Affiliations

Soon will be listed here.

Abstract

Liver ischemia/reperfusion injury (LIRI) is a common complication of liver surgery, and affects liver function post‑transplantation. However, the precise mechanism underlying LIRI has not yet been completely elucidated. Previous studies have demonstrated the involvement of a number of microRNAs (miRNAs/miRs) in liver pathophysiology. The objective of the present study was to determine the potential function and mechanism of miR‑101‑mediated regulation of autophagy in LIRI. Compared with the sham‑treated group, a significant decrease in miR‑101 and mechanistic target of rapamycin (mTOR) expression levels following ischemia/reperfusion (IR) were observed, along with an increased number of autophagosomes (P<0.001). The exogenous overexpression of miR‑101 has been demonstrated to inhibit autophagy during the LIRI response and the levels of mTOR and phosphorylated (p)‑mTOR expression are correspondingly elevated. However, compared with the miR‑NC group, miR‑101 silencing was associated with reduced mTOR and p‑mTOR levels and increased autophagy, as indicated by the gradual increase in the levels of the microtubule‑associated protein 1 light II (LC3II). The peak levels of LC3II were observed 12 h subsequent to reperfusion, which coincided with the lowest levels of miR‑101. In addition, inhibition of autophagy by 3‑methyladenine significant enhanced the protective effect of miR‑101 against LIRI, compared with the IR group (P<0.001). Altogether, miR‑101 attenuates LIRI by inhibiting autophagy via activating the mTOR pathway.

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References

Ohsumi Y . Historical landmarks of autophagy research. Cell Res. 2013; 24(1):9-23. PMC: 3879711. DOI: 10.1038/cr.2013.169. View

Xiao Q, Ye Q, Wang W, Fu B, Xia Z, Liu Z . Mild hypothermia pretreatment protects hepatocytes against ischemia reperfusion injury via down-regulating miR-122 and IGF-1R/AKT pathway. Cryobiology. 2017; 75:100-105. DOI: 10.1016/j.cryobiol.2017.01.005. View

Kim J, Kundu M, Viollet B, Guan K . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011; 13(2):132-41. PMC: 3987946. DOI: 10.1038/ncb2152. View

Xu Y, An Y, Wang Y, Zhang C, Zhang H, Huang C . miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol Rep. 2013; 29(5):2019-24. DOI: 10.3892/or.2013.2338. View

Yang W, Chen J, Meng Y, Chen Z, Yang J . Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver. Int J Mol Sci. 2018; 19(5). PMC: 5983804. DOI: 10.3390/ijms19051302. View

Yang Y, Liang C . MicroRNAs: an emerging player in autophagy. ScienceOpen Res. 2016; 2015. PMC: 4700926. DOI: 10.14293/S2199-1006.1.SOR-LIFE.A181CU.v1. View

Chen J, Yu Y, Li S, Liu Y, Zhou S, Cao S . MicroRNA-30a ameliorates hepatic fibrosis by inhibiting Beclin1-mediated autophagy. J Cell Mol Med. 2017; 21(12):3679-3692. PMC: 5706581. DOI: 10.1111/jcmm.13278. View

Halazun K, Quillin R, Rosenblatt R, Bongu A, Griesemer A, Kato T . Expanding the Margins: High Volume Utilization of Marginal Liver Grafts Among >2000 Liver Transplants at a Single Institution. Ann Surg. 2017; 266(3):441-449. DOI: 10.1097/SLA.0000000000002383. View

Lin C, Liu L, Addison J, Wonderlin W, Ivanov A, Ruppert J . A KLF4-miRNA-206 autoregulatory feedback loop can promote or inhibit protein translation depending upon cell context. Mol Cell Biol. 2011; 31(12):2513-27. PMC: 3133414. DOI: 10.1128/MCB.01189-10. View

10.

Kim H, Joe Y, Yu J, Chen Y, Jeong S, Mani N . Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway. Biochim Biophys Acta. 2015; 1852(7):1550-9. DOI: 10.1016/j.bbadis.2015.04.017. View

11.

Coleman M, Olivier A, Jacobus J, Mapuskar K, Mao G, Martin S . Superoxide mediates acute liver injury in irradiated mice lacking sirtuin 3. Antioxid Redox Signal. 2013; 20(9):1423-35. PMC: 3936509. DOI: 10.1089/ars.2012.5091. View

12.

Zhang S, Wang M, Li Q, Zhu P . MiR-101 reduces cell proliferation and invasion and enhances apoptosis in endometrial cancer via regulating PI3K/Akt/mTOR. Cancer Biomark. 2017; 21(1):179-186. DOI: 10.3233/CBM-170620. View

13.

Carthew R, Sontheimer E . Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009; 136(4):642-55. PMC: 2675692. DOI: 10.1016/j.cell.2009.01.035. View

14.

Li C, Ng K, Shao Y, Liu X, Ling C, Ma Y . The inhibition of aldose reductase attenuates hepatic ischemia-reperfusion injury through reducing inflammatory response. Ann Surg. 2014; 260(2):317-28. DOI: 10.1097/SLA.0000000000000429. View

15.

Valera E, Spencer B, Mott J, Trejo M, Adame A, Mante M . MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci. 2017; 10:329. PMC: 5650998. DOI: 10.3389/fnmol.2017.00329. View

16.

Xu L, Beckebaum S, Iacob S, Wu G, Kaiser G, Radtke A . MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity. J Hepatol. 2013; 60(3):590-8. DOI: 10.1016/j.jhep.2013.10.028. View

17.

Rautou P, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R . Autophagy in liver diseases. J Hepatol. 2010; 53(6):1123-34. DOI: 10.1016/j.jhep.2010.07.006. View

18.

Liu D, Tang H, Li X, Deng M, Wei N, Wang X . Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease. Mol Ther. 2017; 25(3):752-764. PMC: 5363202. DOI: 10.1016/j.ymthe.2017.01.018. View

19.

Ji H, Shen X, Gao F, Ke B, Freitas M, Uchida Y . Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury. Hepatology. 2010; 52(4):1380-9. PMC: 2947605. DOI: 10.1002/hep.23843. View

20.

Li S, Zhang J, Wang Z, Wang T, Yu Y, He J . MicroRNA-17 regulates autophagy to promote hepatic ischemia/reperfusion injury via suppression of signal transductions and activation of transcription-3 expression. Liver Transpl. 2016; 22(12):1697-1709. DOI: 10.1002/lt.24606. View