Targeting fatty acid synthase reduces aortic atherosclerosis and inflammation

Fatty acid synthase (FAS) is predominantly expressed in the liver and adipose tissue. It plays vital roles in de novo synthesis of saturated fatty acids and regulates insulin sensitivity. We previously demonstrated that serum circulating FAS (cFAS) is a clinical biomarker for advanced atherosclerosis, and that it is conjugated to low-density lipoproteins (LDL). However, it remains unknown whether cFAS can directly impact atheroprogression. To investigate this, we evaluate whether cFAS impacts macrophage foam cell formation – an important cellular process leading to atheroprogression. Macrophages exposed to human serum containing high levels of cFAS show increased foam cell formation as compared to cells exposed to serum containing low levels of cFAS. This difference is not observed using serum containing either high or low LDL. Pharmacological inhibition of cFAS using Platensimycin (PTM) decreases foam cell formation in vitro. In Apoe^−/− mice with normal FAS expression, administration of PTM over 16 weeks along with a high fat diet decreases cFAS activity and aortic atherosclerosis without affecting circulating total cholesterol. This effect is also observed in Apoe^−/− mice with liver-specific knockout of hepatic Fasn. Reductions in aortic root plaque are associated with decreased macrophage infiltration. These findings demonstrate that cFAS plays an important role in arterial atheroprogression.