Apolipoprotein D Transgenic Mice Develop Hepatic Steatosis through Activation of PPAR? and Fatty Acid Uptake

Labrie, Marilyne; Lalonde, Simon; Najyb, Ouafa; Thiery, Maxime; Daneault, Caroline; Des Rosiers, Chrisitne; Rassart, Eric; Mounier, Catherine

To support our hypothesis on the role of apoD in AA transport and the consequence on PPARγ activation, we evaluated the total concentration of AA (free and bound to TG and PL) in plasma and liver of WT and H-apoD Tg mice using quantitative isotope dilution gas chromatography-mass spectrometry. Our data show that the absolute AA concentration is significantly decreased in the plasma of H-apoD Tg compared to WT mice. Consequently, we also observed a significant enrichment in hepatic AA in the total fatty acid pool (Fig 7) . However, the prostaglandin E2 concentration is similar between WT and H-apoD Tg mice (S2 Fig) Taken together, our study shows that overexpression of H-apoD leads to increased hepatic PPARγ expression and subsequent activation of the proteins involved in LD formation. This effect is also associated with an elevation of fatty acid uptake while lipogenesis remains unaffected. Because the metabolic syndrome is mild, the slight increase in the mitochondrial β- oxidation is probably a compensatory mechanism. Experiments performed with HepG2 cells suggest that the hepatic steatosis is a result of an increased AA by apoD in the liver as confirmed by the enrichment of hepatic AA in H-apoD mice. This leads to PPARγ transcriptional activation and downstream effects such as the mild metabolic syndrome and the associated insulin resistance.