PROJECT SUMMARY Alterations in the control of lipid homeostasis can lead to cardiometabolic diseases, including atherosclerosis, the most common cause of mortality in Western societies. Our previous studies have demonstrated the importance of miRNAs in regulating high-density lipoprotein (HDL)-C and LDL-C. Work from our group and others identified miR-33a/b as key regulators of cellular cholesterol efflux and uptake, HDL biogenesis and fatty acid metabolism. Notably, we have recently discovered that miR-33 and the nuclear receptor liver X receptor (LXR) regulates the expression of transmembrane protein 86a (TMEM86a), which is a lysoplasmalogenase that regulates plasmalogen (phospholipid) metabolism. This finding is highly relevant given the key role of these phospholipids as reservoir of polyunsaturated fatty acids, which are the precursors of bioactive lipids that control inflammation resolution. Plasmalogen/lysoplasmalogen content in cells can also regulate membrane fluidity, which may contribute to cytokine-mediated inflammatory responses, efferocytotic capacity, ER stress, lipid peroxidation, and cellular cholesterol efflux in macrophages. Notably, TMEM86a is highly expressed in human and mouse atherosclerotic lesions, suggesting a relevant role for this enzyme in regulating macrophage immunometabolic response during atherosclerosis. Together, these novel findings strongly suggest that LXR/miR-33/TMEM86a signalling pathway might contribute to the chronic vascular inflammation observed in atherosclerotic lesions. To investigate the functional relevance of TMEM86a in regulating macrophage phospholipid metabolism during the progression of atherosclerosis, we have recently generated a mouse model that lack the expression of TMEM86a in macrophages. Using these mice and cutting-edge techniques (genomics and metabolomics), we will elucidate the contribution of LXR/miR-33/TMEM86a pathway in atherogenesis.