Apolipoprotein D overexpression alters hepatic prostaglandin and omega fatty acid metabolism during the development of a non-inflammatory hepatic steatosis

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. Overexpression of ApoD in mouse neural tissue induces the development of a non-inflammatory hepatic steatosis in 12-month-old transgenic animals. Previous data indicates that accumulation of arachidonic acid, ApoD's preferential ligand, and overactivation of PPARγ are likely the driving forces in the development of the pathology. However, the lack of inflammation under those conditions is surprising. Hence, we further investigated the apparent repression of inflammation during hepatic steatosis development in aging transgenic animals. The earliest modulation of lipid metabolism and inflammation occurred at 6 months with a transient overexpression of L-PGDS and concomitant overproduction of 15d-PGJ2, a PPARγ agonist. Hepatic lipid accumulation was detectable as soon as 9 months. Inflammatory polarization balance varied in time, with a robust anti-inflammatory profile at 6 months coinciding with 15d-PGJ2 overproduction. Omega-3 and omega-6 fatty acids were preferentially stored in the liver of 12-month-old transgenic mice and resulted in a higher omega-3/omega-6 ratio compared to wild type mice of the same age. Thus, inflammation seems to be controlled by several mechanisms in the liver of transgenic mice: first by an increase in 15d-PGJ2 production and later by a beneficial omega-3/omega-6 ratio. PPARγ seems to play important roles in these processes. The accumulation of several omega fatty acids species in the transgenic mouse liver suggests that ApoD might bind to a broader range of fatty acids than previously thought. •Apolipoprotein D (ApoD) overexpression in mouse neural tissue induces the development of a non-inflammatory hepatic steatosis•Inflammation profile of hepatic tissue was evaluated during steatosis development in aging transgenic animals•A robust anti-inflammatory profile, coinciding with 15d-PGJ2 overproduction, was observed in 6-month-old transgenic mice•A high omega-3/omega-6 fatty acid ratio was observed in 12-month-old transgenic mice•Omega fatty acids accumulation pattern in transgenic mouse livers suggests that ApoD binds to a broader range of fatty acids