George J Ventro1, Yingkui Yang2, Min Chen2, Carroll M Harmon3. 1. State University of New York, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Department of Surgery, Buffalo, NY; Women and Children's Hospital of Buffalo, Buffalo, NY. 2. State University of New York, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Department of Surgery, Buffalo, NY. 3. State University of New York, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Department of Surgery, Buffalo, NY; Women and Children's Hospital of Buffalo, Buffalo, NY. Electronic address: charmon@kaleidahealth.org.
Abstract
PURPOSE: Parenteral nutrition associated liver disease (PNALD) develops in a subset of children receiving parenteral nutrition for intestinal failure. Omegaven™ is an omega-3 fatty acid (Ω3FA) lipid emulsion high in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) that can lessen PNALD. Inflammatory cytokines (IL-1, TNF-α, TGF-β) are elevated in PNALD and can decrease paraoxonase 1 protein expression (PON1). We sought to determine the effect of Omegaven™, EPA, and DHA on inflammatory cytokines TNF-α, IL-1, and TGF-β via ERK1/2 and p-Smad2/3 signaling pathways as well as the changes in intracellular PON1 protein expression as a potential mechanism explaining the protective effects of Omegaven™ and Ω3FA. METHODS: HepG2 cells were cultured with each cytokine and Omegaven™, or EPA and DHA, or Intralipid™. P-Smad2/3 and PON1 protein levels were measured by Western blotting. ERK1/2 signaling was studied using homogenous time resolved fluorescence. RESULTS: Omegaven™ decreased TGF-β mediated Smad2/3 signaling by 30% (70% of control ±12, p<0.03). Omegaven™ decreased IL-1 and TNF-α mediated ERK1/2 signaling (0.49 fold ±0.09, p<0.05 and 0.22±0.05, p<0.05) compared to control. CONCLUSION: Our results describe potential mechanisms by which Omegaven™ and Ω3FA can be hepatoprotective in the setting of PNALD by abating inflammatory cytokine signaling.
PURPOSE: Parenteral nutrition associated liver disease (PNALD) develops in a subset of children receiving parenteral nutrition for intestinal failure. Omegaven™ is an omega-3 fatty acid (Ω3FA) lipid emulsion high in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) that can lessen PNALD. Inflammatory cytokines (IL-1, TNF-α, TGF-β) are elevated in PNALD and can decrease paraoxonase 1 protein expression (PON1). We sought to determine the effect of Omegaven™, EPA, and DHA on inflammatory cytokines TNF-α, IL-1, and TGF-β via ERK1/2 and p-Smad2/3 signaling pathways as well as the changes in intracellular PON1 protein expression as a potential mechanism explaining the protective effects of Omegaven™ and Ω3FA. METHODS: HepG2 cells were cultured with each cytokine and Omegaven™, or EPA and DHA, or Intralipid™. P-Smad2/3 and PON1 protein levels were measured by Western blotting. ERK1/2 signaling was studied using homogenous time resolved fluorescence. RESULTS: Omegaven™ decreased TGF-β mediated Smad2/3 signaling by 30% (70% of control ±12, p<0.03). Omegaven™ decreased IL-1 and TNF-α mediated ERK1/2 signaling (0.49 fold ±0.09, p<0.05 and 0.22±0.05, p<0.05) compared to control. CONCLUSION: Our results describe potential mechanisms by which Omegaven™ and Ω3FA can be hepatoprotective in the setting of PNALD by abating inflammatory cytokine signaling.
Authors: Licínia Ganança; Hanga C Galfalvy; Sebastian Cisneros-Trujillo; Zahra Basseda; Thomas B Cooper; Xinguo Ren; Maria Luisa Figueira; Maria A Oquendo; J John Mann; M Elizabeth Sublette Journal: J Psychiatr Res Date: 2020-12-17 Impact factor: 4.791