Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells
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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.
• 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.
KeywordsAdiponectin Hepatic stellate cell Inducible nitric oxide synthase The AMP-activated protein kinase
- AD KO
Adenosine monophosphate-activated protein kinase
Alpha smooth muscle actin
Extracellular signal-regulated kinase1/2
Hepatic stellate cells
Inducible nitric oxide synthase
c-Jun terminal kinase
NG-nitro-l-arginine methyl ester, hydrochloride
Ras-mitogen-activated protein kinase
Neuronal nitric oxide synthase
Nuclear factor kappa B
Platelet-derived growth factor
Sinusoidal endothelial cells
Small interfering RNA
S-methylisothiourea hemisulfate salt
Transforming growth factor beta 1
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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