Molecular impact of omega 3 fatty acids on lipopolysaccharide-mediated liver damage

Growing evidence suggests that omega 3 fatty acid containing lipid emulsions have a beneficial effect on parenteral nutrition associated liver disease (PNALD). However, the cellular and molecular mechanisms responsible for this effect are unclear. In this study, we investigated whether Omegaven™ fish oil emulsion could inhibit lipopolysaccharidase (LPS) mediated liver damage.

We examined the effects of Omegaven™ and LPS alone and synergistically on hepatic paraoxonase 1 (PON1), a potent antioxidant protein, ERK1/2 activity, and TLR4 regulation.

LPS did not alter PON1 release from HepG2 cells but did significantly decrease PON1 protein synthesis (44%, P<0.05). Omegaven™ alone had no direct effect on PON1 release. However, it did significantly reverse LPS-mediated decrease in PON1 protein levels (control: 100%; LPS alone: 56+/4%; LPS+Omegaven™: 87+/6%, P<0.05). Furthermore, molecular analysis indicated that Omegaven™ blocked LPS-mediated increase in ERK1/2 activity (35% increase), an important LPS signal transduction pathway. TLR4, the receptor for LPS, was down-regulated in the presence of Omegaven™.

Omegaven™ may be beneficial in patients with PNAC because of its ability to reverse LPS-mediated inhibition of antioxidant promoting PON1 expression, and this activity may be in part mediated by the ERK1/2 pathway.