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.
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.
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.
Our results describe potential mechanisms by which Omegaven™ and Ω3FA can be hepatoprotective in the setting of PNALD by abating inflammatory cytokine signaling.