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

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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.

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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

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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.

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    Authors and Affiliations

    1. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

      Zhixia Dong

    2. Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia

      Zhixia Dong, Lin Su, Saeed Esmaili, Tristan J. Iseli, Mehdi Ramezani-Moghadam, Liangshuo Hu, Jacob George & Jianhua Wang

    3. State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, the University of Hong Kong, Hong Kong, Hong Kong

      Aimin Xu

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    Zhixia Dong and Lin Su contributed equally to this work.

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    Dong, Z., Su, L., Esmaili, S. et al. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells. J Mol Med 93, 1327–1339 (2015). https://doi.org/10.1007/s00109-015-1313-z

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