Abstract 311: Fatty Acid Synthase Targeting Reduces Aortic Atherosclerosis And Inflammation

Abstract

Fatty acid synthase (FAS) catalyzes the elongation of saturated fatty acids. FAS is elevated in liver and adipose tissue in the setting of diabetes, and serum circulating FAS (cFAS) is a marker of peripheral arterial disease. The natural antibiotic Platensimycin (PTM) competitively inhibits FAS. However, the impact of chemical FAS inhibition on atherosclerosis is unknown. We hypothesized that PTM and a liver-specific knockdown of FAS would reduce the burden of aortic atherosclerosis. ApoE-/- mice were placed on a 42% high-fat diet (HFD) with or without PTM (100mpk) for 16 weeks. Similarly, ApoE-/- mice with or without liver-specific knockdown of FAS ( ApoE-/- FasL-/- vs ApoE-/- FasL+/+ ) were placed on a 42% HFD for 16 weeks (Fig. A). Tissue FAS, cFAS, and serum triglycerides (TG) content were measured. FAS/cFAS activity was evaluated with a modified measurement of malonyl-CoA consumption of NADPH, and normalized to content. At 16 weeks, mouse aortas were harvested and stained with oil-red O and CD68 to assess the burden of atherosclerosis and inflammation. Comparisons between murine groups were analyzed using Mann-Whitney and Student t-tests. ApoE-/- mice treated with PTM, significantly reduced tissue FAS and serum cFAS activity (p<0.05), and significantly reduced serum TG (p<0.01). ApoE-/- FasL-/- mice demonstrated increased adipose FAS content and activity (p<0.05), reduced cFAS activity (p<0.05), and increased serum TG (p<0.05). Targeting FAS/cFAS with PTM or in FasL-/- led to decrease in overall total aortic plaque, particularly in the low-resistance thoracic aorta (B; p<0.05).Targeting FAS/cFAS also demonstrated reduced aortic root plaque, and macrophage content(C; p<0.05).This study reveals that selective targeting of FAS/cFAS either with PTM of via liver knockdown, appear to significantly alter serum lipid profiles, aortic atherosclerosis, and plaque inflammation. Thus, FAS/cFAS may be an important therapeutic target to inhibit atheroprogression.