Fatty acid synthase global inducible knockout does not alter brain fatty acid concentrations but attenuates cholesterol synthesis in the adult mouse

Abstract

Fatty acid (FA) de novo synthesis, also called de novo lipogenesis (DNL), has a central role in peripheral energy storage and provides structural components for lipid membranes. However, less is known regarding its contribution to brain FA homeostasis. DNL is catalyzed by fatty acid synthase (FAS), which is a multifunctional enzyme expressed in all mammalian tissues. In the present study, we addressed, for the first time, the effect of FAS gene global conditional inducible knockout (Fasn KO) on the adult brain FA concentrations and lipid metabolism. We achieved a 67 % reduction in the brain FAS protein levels, with a significant reduction in total FA synthesis measured by ³H₂O incorporation into FA, which was lethal 10 days after gene recombination induction. However, the concentrations of all 44 FA molecular species assayed by LC-MS were unchanged in the brain. We also did not detect changes in the major proteins involved in FA synthesis regulation and remodeling, including peroxisome proliferator-activated receptor α (PPARα), PPARδ, FA desaturase-1, -2, and -3, and Stearoyl-CoA desaturase 1 but did observe a decrease in PPARɣ levels. In addition, brain cholesterol synthesis was significantly reduced in the Fasn KO brains. These data indicate that DNL is not required to maintain measured FA concentrations in the brain and that dietary FA and liver-derived pools might compensate for decreased brain DNL within the duration of the study. However, our data indicate a possible role of FAS in PPARɣ regulation and cholesterol metabolism in the adult brain.