title: Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice.
abstract: Nogo-B (reticulon 4B) accentuates hepatic fibrosis and cirrhosis, but the mechanism remains unclear. The aim of this study was to identify the role of Nogo-B in hepatic stellate cell (HSC) apoptosis in cirrhotic livers. Cirrhosis was generated by carbon tetrachloride inhalation in wild-type (WT) and Nogo-A/B knockout (Nogo-B KO) mice. HSCs were isolated from WT and Nogo-B KO mice and cultured for activation and transformation to myofibroblasts (MF-HSCs). Human hepatic stellate cells (LX2 cells) were used to assess apoptotic responses of activated HSCs after silencing or overexpressing Nogo-B. Livers from cirrhotic Nogo-B KO mice showed significantly reduced fibrosis (P < 0.05) compared with WT mice. Apoptotic cells were more prominent in fibrotic areas of cirrhotic Nogo-B KO livers. Nogo-B KO MF-HSCs showed significantly increased levels of apoptotic markers, cleaved poly (ADP-ribose) polymerase, and caspase-3 and -8 (P < 0.05) compared with WT MF-HSCs in response to staurosporine. Treatment with tunicamycin, an endoplasmic reticulum stress inducer, increased cleaved caspase-3 and -8 levels in Nogo-B KO MF-HSCs compared with WT MF-HSCs (P < 0.01). In LX2 cells, Nogo-B knockdown enhanced apoptosis in response to staurosporine, whereas Nogo-B overexpression inhibited apoptosis. The absence of Nogo-B enhances apoptosis of HSCs in experimental cirrhosis. Selective blockade of Nogo-B in HSCs may represent a potential therapeutic strategy to mitigate liver fibrosis.
authors: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors: Keitaro
authors: K
authors: Tashiro
authors: Ayano
authors: A
authors: Satoh
authors: Teruo
authors: T
authors: Utsumi
authors: Chuhan
authors: C
authors: Chung
authors: Yasuko
authors: Y
authors: Iwakiri
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009185:Myelin Proteins / Q000172:deficiency* / Q000378:metabolism; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000070798:Nogo Proteins; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse; D019311:Staurosporine