caa a22 4500 605543275 CHVBK 20210128100925.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s00109-015-1313-z doi (NATIONALLICENCE)springer-10.1007/s00109-015-1313-z Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells [Elektronische Daten] [Zhixia Dong, Lin Su, Saeed Esmaili, Tristan Iseli, Mehdi Ramezani-Moghadam, Liangshuo Hu, Aimin Xu, Jacob George, Jianhua Wang] 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. Springer-Verlag Berlin Heidelberg, 2015 Adiponectin nationallicence Hepatic stellate cell nationallicence Inducible nitric oxide synthase nationallicence The AMP-activated protein kinase nationallicence AD : Adiponectin nationallicence AD KO : Adiponectin knockout nationallicence AMPK : Adenosine monophosphate-activated protein kinase nationallicence αSMA : Alpha smooth muscle actin nationallicence CCL4 : Carbon tetrachloride nationallicence Erk1/2 : Extracellular signal-regulated kinase1/2 nationallicence HSCs : Hepatic stellate cells nationallicence iNOS : Inducible nitric oxide synthase nationallicence JNK : c-Jun terminal kinase nationallicence l -NAME : NG-nitro-l-arginine methyl ester, hydrochloride nationallicence MAPK : Ras-mitogen-activated protein kinase nationallicence NO : Nitric oxide nationallicence nNOS : Neuronal nitric oxide synthase nationallicence NF-κB : Nuclear factor kappa B nationallicence PDGF : Platelet-derived growth factor nationallicence PDTC : Ammonium pyrrolidinedithiocarbamate nationallicence SECs : Sinusoidal endothelial cells nationallicence siRNA : Small interfering RNA nationallicence SMT : S-methylisothiourea hemisulfate salt nationallicence TGFβ1 : Transforming growth factor beta 1 nationallicence WT : Wide type nationallicence Dong Zhixia Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China aut Su Lin Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Esmaili Saeed Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Iseli Tristan Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Ramezani-Moghadam Mehdi Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Hu Liangshuo Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Xu Aimin State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, the University of Hong Kong, Hong Kong, Hong Kong aut George Jacob Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Wang Jianhua Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/12(2015-12-01), 1327-1339 0946-2716 93:12<1327 2015 93 109 https://doi.org/10.1007/s00109-015-1313-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1313-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Dong Zhixia Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Su Lin Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 700 1- Esmaili Saeed Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 700 1- Iseli Tristan Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 700 1- Ramezani-Moghadam Mehdi Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 700 1- Hu Liangshuo Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 700 1- Xu Aimin State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, the University of Hong Kong, Hong Kong, Hong Kong aut NATIONALLICENCE 700 1- George Jacob Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 700 1- Wang Jianhua Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, 2145, Westmead, NSW, Australia aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/12(2015-12-01), 1327-1339 0946-2716 93:12<1327 2015 93 109