Apoptosis

, Volume 19, Issue 1, pp 30–41

MicroRNA-29a protects against acute liver injury in a mouse model of obstructive jaundice via inhibition of the extrinsic apoptosis pathway

Authors

  • Mao-Meng Tiao
    • Department of PediatricsKaohsiung Chang Gung Memorial Hospital and the Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine
  • Feng-Sheng Wang
    • Department of Medical ResearchKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
  • Li-Tung Huang
    • Department of PediatricsKaohsiung Chang Gung Memorial Hospital and the Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine
  • Jiin-Haur Chuang
    • Department of SurgeryKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
  • Ho-Chang Kuo
    • Department of PediatricsKaohsiung Chang Gung Memorial Hospital and the Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine
  • Ya-Ling Yang
    • Department of AnesthesiologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
    • Department of PediatricsKaohsiung Chang Gung Memorial Hospital and the Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine
Original Paper

DOI: 10.1007/s10495-013-0909-4

Cite this article as:
Tiao, M., Wang, F., Huang, L. et al. Apoptosis (2014) 19: 30. doi:10.1007/s10495-013-0909-4

Abstract

Recent studies have shown that microRNA-29 (miR-29) is significantly decreased in liver fibrosis, as demonstrated in human liver cirrhosis, and that its downregulation influences the activation of hepatic stellate cells. In addition, both cleaved caspase-3 production and apoptosis play a role in cholestatic liver injury. However, it is unknown if miR-29 is effective in modulating the extent of injury. We employed miR-29a transgenic mice (miR-29aTg mice) and wild-type (WT) littermates to clarify the role of miR-29 in hepatic injury and fibrogenesis, using the bile duct-ligation (BDL) mouse model. After BDL, all three members of the miR-29 family were significantly downregulated in the livers of WT mice, and miR-29b and miR-29c were significantly downregulated in the livers of the miR-29aTg mice. Liver function, as measured by alanine transaminase and aspartate transaminase activity, was significantly improved in the miR-29aTg mice than in the WT littermates, following 1 week of obstructive jaundice. In addition, overexpression of miR-29a was associated with a significant downregulation of the expression of collagen-1α1, collagen-4α1, phospho-FADD, cleaved caspase-8, cleaved caspase-3, Bax, Bcl-2, PARP, and nuclear factor-κB, as well as an upregulation of phospho-AKT expression. In addition, there were significantly fewer TUNEL-positive liver cells in the miR-29aTg group than in the WT littermates after BDL. Our results indicate that miR-29a decreases cholestatic liver injury and fibrosis after BDL, at least partially, by modulating the extrinsic rather than intrinsic pathway of apoptosis.

Keywords

Caspase Mir-29 Cholestasis TUNEL

Abbreviations

BDL

Bile duct ligation

ECM

Extracellular matrix

HSC

Hepatic stellate cells

LDH

Lactate dehydrogenase

TLR

Toll like receptor

TUNEL

TdT-mediated dUTP biotin nick-end labeling

WT

Wide type

XIAP

X-linked inhibitor of the apoptotic protein

Supplementary material

10495_2013_909_MOESM1_ESM.tif (77 kb)
Fig. S1 Quantitative measurement of collagen-1α1 expression by immunofluorescence staining in liver tissue of miR-29a transgenic mice and WT littermates underwent sham operation and bile duct ligation (BDL). Data are expressed as mean ± standard error in 4 samples from miR-29a transgenic mice and 4 samples from WT littermates (TIFF 76 kb)
10495_2013_909_MOESM2_ESM.tif (1.9 mb)
Fig. S2 Immunoreactive caspase 8 staining between miR-29aTg mice and wild type littermates. There was significantly higher caspase-8 immunoreactivity in the liver tissue of the sham-operated and BDL groups than in the control group, which was expressed constantly in the cytoplasm of hepatocytes (arrowhead). Moreover, overexpression of miR-29a decreased the expression of caspase-8 and caspase-3 after BDL (TIFF 1900 kb)
10495_2013_909_MOESM3_ESM.tif (595 kb)
Fig. S3 Comparison of the X-linked inhibitor of the apoptotic protein (XIAP) expression by western blot in liver tissue of miR-29a transgenic mice and WT littermates that underwent sham operation and bile duct ligation (BDL). There were significantly downregulated XIAP protein expression in both miR-29aTg mice and WT littermates after BDL. However, overexpression did not change of XIAP protein expression after BDL. Data are expressed as mean ± standard error in 8 samples from miR-29a transgenic mice and 6 samples from WT littermates (TIFF 595 kb)

Copyright information

© Springer Science+Business Media New York 2013