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Journal of Molecular Medicine

, Volume 93, Issue 12, pp 1327–1339 | Cite as

Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells

  • Zhixia Dong
  • Lin Su
  • Saeed Esmaili
  • Tristan J. Iseli
  • Mehdi Ramezani-Moghadam
  • Liangshuo Hu
  • Aimin Xu
  • Jacob George
  • Jianhua Wang
Original Article

Abstract

Adiponectin protects against liver fibrosis, but the mechanisms have not been fully elucidated. Here, we showed that adiponectin upregulated inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) and protein expression in hepatic non-parenchymal cells, particularly in hepatic stellate cells (HSCs), and increased nitric oxide (NO2−/NO3−) concentration in HSC-conditioned medium. Adiponectin attenuated HSC proliferation and migration but promoted apoptosis in a NO-dependent manner. More advanced liver fibrosis with decreased iNOS/NO levels was observed in adiponectin knockout mice comparing to wide-type mice when administered with CCI4 while NO donor supplementation rescued the phenotype. Further experiments demonstrated that adiponectin-induced iNOS/NO system activation is mediated through adipoR2-AMPK-JNK/Erk1/2-NF-κB signaling. These data suggest that adiponectin inhibits HSC function, further limiting the development of liver fibrosis at least in part through adiponectin-induced NO release. Therefore, adiponectin-mediated NO signaling may be a novel target for the treatment of liver fibrosis.

Key messages

• Adiponectin activates HSC iNOS/NO and SEC eNOS/NO systems.

• Adiponectin inhibits HSC proliferation and migration but promotes its apoptosis.

• Adiponectin inhibits CCL4-induced liver fibrosis by modulation of liver iNOS/NO.

• Adiponectin stimulates HSC iNOS/NO via adipoR2-AMPK-JNK/ErK1/2-NF-κB pathway.

Keywords

Adiponectin Hepatic stellate cell Inducible nitric oxide synthase The AMP-activated protein kinase 

Abbreviations

AD

Adiponectin

AD KO

Adiponectin knockout

AMPK

Adenosine monophosphate-activated protein kinase

αSMA

Alpha smooth muscle actin

CCL4

Carbon tetrachloride

Erk1/2

Extracellular signal-regulated kinase1/2

HSCs

Hepatic stellate cells

iNOS

Inducible nitric oxide synthase

JNK

c-Jun terminal kinase

l-NAME

NG-nitro-l-arginine methyl ester, hydrochloride

MAPK

Ras-mitogen-activated protein kinase

NO

Nitric oxide

nNOS

Neuronal nitric oxide synthase

NF-κB

Nuclear factor kappa B

PDGF

Platelet-derived growth factor

PDTC

Ammonium pyrrolidinedithiocarbamate

SECs

Sinusoidal endothelial cells

siRNA

Small interfering RNA

SMT

S-methylisothiourea hemisulfate salt

TGFβ1

Transforming growth factor beta 1

WT

Wide type

Notes

Acknowledgments

We thank Xin Wang (Flow Cytometry Facility, Westmead Millennium Institute) and Hong Yu (Microscopy Unit, Westmead Millennium Institute) for technical assistance. This study was supported by the National Health and Medical Research Council of Australia (AP1004595 and a Program Grant 1053206) and the Robert W. Storr Bequest to the University of Sydney.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

109_2015_1313_MOESM1_ESM.pdf (653 kb)
ESM 1 (PDF 653 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Zhixia Dong
    • 1
    • 2
  • Lin Su
    • 2
  • Saeed Esmaili
    • 2
  • Tristan J. Iseli
    • 2
  • Mehdi Ramezani-Moghadam
    • 2
  • Liangshuo Hu
    • 2
  • Aimin Xu
    • 3
  • Jacob George
    • 2
  • Jianhua Wang
    • 2
  1. 1.Department of Gastroenterology, Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Storr Liver Unit, Westmead Millennium Institute and Westmead HospitalUniversity of SydneyWestmeadAustralia
  3. 3.State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicinethe University of Hong KongHong KongHong Kong

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