MicroRNA-124a contributes to glucocorticoid resistance in acute-on-chronic liver failure by negatively regulating glucocorticoid receptor alpha.

Xin Wang, Hongrui Xu, Yadong Wang, Chuan Shen, Luyuan Ma, Caiyan Zhao

Annals of hepatology 2020 Mar - Apr

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Glucocorticoid resistance frequently associating with inflammation, may severely compromise the therapeutic effect of glucocorticoids. In this study, we aimed to investigate the regulation of glucocorticoid resistance by microRNA-124a (miR-124a) in patients with acute-on-chronic liver failure (ACLF). The miR-124a levels and glucocorticoid receptor alpha (GRα) expressions in peripheral blood monocytes and liver tissues were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot analyses in the following four groups: healthy controls (HC), moderate chronic hepatitis B (CHB) patients, hepatitis B virus-related ACLF (HBV-ACLF) patients, and alcohol-induced ACLF (A-ACLF) patients. In addition, the serum miR-124a levels and multiple biochemical indices were determined. The effects of miR-124a transfection on GRα expression were assayed by qRT-PCR and western blotting in U937 and HepG2 cells stimulated with lipopolysaccharide (LPS). Compared with the CHB patients and HC, the miR-124a levels in HBV-ACLF and A-ACLF patients increased, while GRα expressions decreased. No significant differences in miR-124a levels and GRα expressions were observed between the HBV-ACLF and A-ACLF patients. For the ACLF patients, miR-124a level was negatively related to GRα expression in monocytes and positively correlated with the inflammatory factors such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). In U937 and HepG2 cells, LPS stimulated miR-124a levels but inhibited GRα expressions; meanwhile, increasing miR-124a levels reduced GRα expressions, and inhibiting miR-124a levels increased GRα expressions. This study provides evidence that GRα expression was negatively regulated by miR-124a, which primarily determines the extent of acquired glucocorticoid resistance in ACLF. Copyright © 2019. Published by Elsevier España, S.L.U.

Citation

Xin Wang, Hongrui Xu, Yadong Wang, Chuan Shen, Luyuan Ma, Caiyan Zhao. MicroRNA-124a contributes to glucocorticoid resistance in acute-on-chronic liver failure by negatively regulating glucocorticoid receptor alpha. Annals of hepatology. 2020 Mar - Apr;19(2):214-221