title: Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells.
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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Lin
authors.initials: L
authors.lastname: Su
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Saeed
authors.initials: S
authors.lastname: Esmaili
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Iseli
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ramezani-Moghadam
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Liangshuo
authors.initials: L
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, the University of Hong Kong, Hong Kong, Hong Kong.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW, 2145, Australia. jianhua.wang@sydney.edu.au.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
mesh_terms: D052242:Adiponectin / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D054419:Receptors, Adiponectin / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D052242:Adiponectin; D054419:Receptors, Adiponectin; D051996:Transcription Factor RelA; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: Adiponectin; Hepatic stellate cell; Inducible nitric oxide synthase; The AMP-activated protein kinase