Atherosclerotic Cardiovascular Disease is a major cause of death in patients with diabetes and it is only in part controlled by available therapeutics agents. There is an ongoing need to better identify high-risk individuals for therapy or prevention of CVD who are missed by current risk stratification methods. In a pilot study including subjects (n=30) with or without carotid atherosclerosis, paired-matched for major variables, we found that circulating 3-hydroxyisobutyrate (3HIB) metabolite, a derivative from valine catabolism, is significantly higher in subjects with vascular damage. To investigate the role of 3HIB in the context of macrovascular complications, we have designed a complementary study in vascular cellular models in vitro, including endothelial cells and macrophages derived foam cells. First, we tested the dose response effects of 3HIB on endothelial activation markers. Results show that 3-HIB is able to significantly increase the expression of VCAM (p<0,0001) and CD62E (p<0,001) endothelial adhesion molecules and CCL2 (p<0,0001) inflammatory cytokine, associated with increased monocyte adhesion (p<0.001). Next, we evaluated the role of 3-HIB on THP-1 derived macrophages. Macrophages are directly involved in atherosclerosis and actively participate in lipoprotein ingestion and accumulation giving rise to foam cells filled with lipid droplets. Accumulation of foam cells contributes to lipid storage and atherosclerotic plaque growth. Macrophages therefore represent attractive targets for development of anti-atherosclerotic therapy. Our results show that in THP-1 derived macrophages, a treatment with 3HIB, in combination or not with palmitate, a saturated long chain fatty acid, increased fatty acid uptake, intracellular trafficking and storage, at least in part through the modulation of fatty acid binding protein 4 (FABP4) mRNA expression (p<0,05) and lipid droplet synthesis. In conclusion, our results suggest that 3HIB could fill the gap in the needed of a specific biomarker able to accelerate crucial cellular mechanisms involved in atherogenic development.