In the present study, we examined: i) whether CGI-58−/− macrophages mimic the TG accumulation phenotype observed in ATGL−/− macrophages; ii) whether CGI-58 deficiency affects macrophage function; and iii) whether the altered phenotype culminates in increased atherosclerosis susceptibility in macCGI-58/ApoE-double KO (DKO) animals. This evidence concerns the gene PNPLA2 and atherosclerosis.