Atherosclerosis is the leading cause of cardiovascular disease (CVD) and the leading reason behind mortality and morbidity in Western countries. The role of long noncoding RNAs (lncRNAs) in CVD is still unexplored with inadequate research on the involvement of lncRNAs in atherogenesis. We found the lncRNA DAPK1-IT1 and lipoprotein lipase (LPL) to be up-regulated in THP-1 macrophage-derived foam cells. We demonstrated that DAPK1-IT1 mediated its promoting effect on LPL expression via regulating an intermediary miRNA hsa-miR-590-3p. This DAPK1-IT1/hsa-miR-590-3p/LPL axis regulates cholesterol metabolism and the inflammatory response in macrophages in vitro. Overexpressing LPL using lentiviral vectors led to decreased circulation of high-density lipoprotein cholesterol (HDL-C), increased circulation of low-density lipoprotein cholesterol (LDL-C) and very-LDL-C (VLDL-C), increased circulating pro-inflammatory cytokine levels (IL-1 beta, IL-6, TNF-alpha), and enhanced atherogenesis in apolipoprotein E-deficient (apoE(-/-)) mice. In sum, the DAPK1-IT1/hsa-miR-590-3p/LPL axis regulates cholesterol metabolism and the inflammatory response in macrophages and may contribute to atherogenesis in vivo. These findings suggest this axis may be a promising therapeutic target in ameliorating CVD. (C) 2019 Elsevier Inc. All rights reserved.