Targeting fatty acid synthase reduces aortic atherosclerosis and inflammation

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Metabolic Diseases

Background:

• Fatty acid synthase (FAS) is crucial for fatty acid synthesis and insulin sensitivity, primarily in the liver and adipose tissue.
• Serum circulating FAS (cFAS), conjugated to LDL, was previously identified as a biomarker for advanced atherosclerosis.
• The direct impact of cFAS on the cellular mechanisms of atheroprogression remained unclear.

Purpose of the Study:

• To investigate the direct role of cFAS in macrophage foam cell formation.
• To determine if cFAS inhibition can mitigate atheroprogression in vivo.

Main Methods:

• Macrophages were exposed to human serum with varying cFAS and LDL levels.
• In vitro foam cell formation was assessed.
• Pharmacological inhibition of cFAS using Platensimycin (PTM) was performed.
• Apoe knockout mice on a high-fat diet were treated with PTM to evaluate aortic atherosclerosis and plaque characteristics.

Main Results:

• Macrophages exposed to high cFAS serum exhibited increased foam cell formation, independent of LDL levels.
• PTM treatment significantly reduced in vitro foam cell formation.
• In vivo, PTM administration in Apoe-/- mice decreased cFAS activity and aortic atherosclerosis, with reduced macrophage infiltration in plaques.
• These effects were consistent even in mice with liver-specific Fasn knockout.

Conclusions:

• Circulating FAS directly contributes to atheroprogression by promoting macrophage foam cell formation.
• Inhibition of cFAS represents a potential therapeutic strategy for reducing atherosclerosis.
• cFAS plays a significant role in the development and progression of arterial disease.