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

Our study describes for the first time a role for apoD in the regulation of PPARγ and the downstream activation of metabolic pathways leading to hepatic steatosis. In Tg mice, elevated apoD expression leads to higher hepatic AA concentration and subsequent activation of the nuclear receptor PPARγ. As a result, PPARγ target genes such as CD36, Plin2, Cide A and Cide C are increased leading to an enhanced LCFA uptake by the hepatocytes and protecting LD against lipolysis by blocking access to lipases. Both PPARγ activation and high CD36 expression induce AMPK expression which leads to increased PPARα expression and its downstream target gene, CPT1 which in turn activates mitochondrial β-oxidation. However, the activation of this compensatory pathway is insufficient to fully inhibit the accumulation of ectopic fat in the liver, but it probably contributes to reduce the progression of hepatic steatosis. Overall, our study highlights a new role for apoD as an AA transporter regulating lipid accumulation in the liver.