miR-223 Deficiency Protects against Fas-Induced Hepatocyte Apoptosis and Liver Injury through Targeting Insulin-Like Growth Factor 1 Receptor

Am J Pathol. 2015 Dec;185(12):3141-51. doi: 10.1016/j.ajpath.2015.08.020.


The biological functions and molecular mechanisms of miR-223 action in liver cells and liver diseases remain unclear. We therefore determined the effect and mechanism of action of miR-233 in Fas-induced hepatocyte apoptosis and liver injury. Wild-type (WT) and miR-223 knockout (KO) mice were treated i.p. with 0.5 μg/g body weight anti-Fas antibody Jo2, and the animals were monitored for survival and the extent of liver injury. Although WT mice died 4 to 6 hours after Jo2 injection (n = 6), all of the miR-223 KO mice (n = 6) survived. In comparison to WT mice, the miR-223 KO mice showed resistance to Fas-induced liver injury, as indicated by less tissue damage under histopathological examination, fewer apoptotic hepatocytes under caspase-3 immunostaining, and less elevation of serum transaminases. miR-223 KO livers showed less caspase-3, caspase-8, and caspase-9 activation and less poly (ADP-ribose) polymerase cleavage compared with WT livers (P < 0.05). Furthermore, tail vein injection of miR-223 lentiviral vector to miR-223 KO mice restored Jo2-induced liver injury. Transfection of miR-223 KO hepatocytes with miR-223 mimic enhanced Jo2-induced activation of caspase-3, caspase-8, and caspase-9, whereas transfection of WT hepatocytes with the miR-223 inhibitor attenuated Jo2-induced apoptosis. These findings demonstrate that miR-223 deficiency protects against Fas-induced hepatocyte apoptosis and liver injury. Further in vitro and in vivo data indicate that miR-223 regulates Fas-induced hepatocyte apoptosis and liver injury by targeting the insulin-like growth factor 1 receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Caspases / metabolism
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Genetic Vectors
  • Hepatocytes / pathology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, IGF Type 1 / physiology*
  • Signal Transduction / physiology
  • Transfection / methods
  • fas Receptor / physiology*


  • MIRN223 microRNA, mouse
  • MicroRNAs
  • fas Receptor
  • Receptor, IGF Type 1
  • Caspases