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.