1. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells.
- Author
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Dong Z, Su L, Esmaili S, Iseli TJ, Ramezani-Moghadam M, Hu L, Xu A, George J, and Wang J
- Subjects
- Adiponectin pharmacology, Animals, Apoptosis drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Disease Models, Animal, Gene Expression Regulation drug effects, Hepatic Stellate Cells drug effects, Liver Cirrhosis chemically induced, MAP Kinase Signaling System drug effects, Mice, Mice, Knockout, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Rats, Receptors, Adiponectin metabolism, Transcription Factor RelA metabolism, Adiponectin genetics, Adiponectin metabolism, Hepatic Stellate Cells metabolism, Liver Cirrhosis genetics, Liver Cirrhosis metabolism, Nitric Oxide metabolism
- Abstract
Unlabelled: 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.
- Published
- 2015
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