sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH
| العنوان: | sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH |
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| المؤلفون: | Guang Liu, Katherine C. Hall, Sarah Jacobson, Mark G. Currie, Renee Sarno, Sylvie G. Bernier, Victoria Catanzano, Ping Y. Zhang, Jaime L. Masferrer |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, soluble guanylate cyclase, praliciguat, Anti-Inflammatory Agents, Enzyme Activators, Inflammation, Nitric Oxide, Nitric oxide, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Soluble Guanylyl Cyclase, Fibrosis, Non-alcoholic Fatty Liver Disease, medicine, Hepatic Stellate Cells, Animals, Humans, Cells, Cultured, Pharmacology, Multidisciplinary, business.industry, AMPK, Biological Sciences, medicine.disease, NASH fibrosis, Coculture Techniques, 030104 developmental biology, Pyrimidines, chemistry, 030220 oncology & carcinogenesis, Hepatic stellate cell, Cancer research, Pyrazoles, Steatosis, medicine.symptom, Signal transduction, business, Myofibroblast, Signal Transduction |
| الوصف: | Significance Nonalcoholic steatohepatitis (NASH) is an increasingly common disease characterized by liver steatosis and inflammation—with fibrosis being an important indicator of disease progression and severity—and is associated with reduced endothelial function and NO–soluble guanylate cyclase (sGC) signaling. Signaling downstream of NO can be restored using praliciguat, an sGC stimulator. Within the liver, stellate cells and myofibroblasts express sGC (unlike hepatocytes) and thus can be stimulated by praliciguat. Increased sGC activity inhibits fibrotic transformation and inflammatory responses in stellate cells potentially through AMPK and SMAD7. The effects on isolated stellate cells translate to human microtissues and in vivo models where treatment with praliciguat reduces inflammation, fibrosis, and steatosis. These preclinical results support further investigation of praliciguat as a potential therapy for NASH/fibrosis. Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO–sGC pathway by praliciguat in both healthy and fibrotic livers. In preclinical models of NASH, praliciguat treatment was associated with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH. |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::07c65ebd93360b967319371168329084 http://europepmc.org/articles/PMC6561202 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....07c65ebd93360b967319371168329084 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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