Proposed metabolic pathways involved in fatty acid and cholesterol accumulation in the livers of n-3 PUFA depleted mice.

The reduction of fatty acid oxidation and the induction of lipogenesis both contribute to the accumulation of lipids in the livers of n-3 PUFA-depleted mice. The reduced fatty acid degradation could result from the inhibition of the PPARα pathway. De novo lipogenesis is promoted through SREBP-1c activation. Data suggest that SREBP-1c activation could result from both increased hepatic 2-AG content and LXR activation. The lower n-3 PUFA content in hepatic phospholipids can lead to higher 2-AG production, which could therefore stimulate CB1 and then SREBP-1c expression. Both hepatic n-3 PUFA depletion and higher cholesterol content contribute to LXR activation. Increased SREBP-2 activation, occurring by an unknown mechanism, could play a role in the increased cholesterol synthesis observed in the n-3 PUFA-depleted livers.