The liver plays a major role in regulating the metabolic fate of lipids and facilitates lipid secretion to peripheral organs in the form of VLDLs or lipid storage in lipid droplets (LDs). Hepatic regulation of excess lipids profoundly influences the development of atherosclerosis; thus, uncovering the regulatory mechanisms underlying lipid storage and secretion pathways may reveal additional therapeutic targets. In this issue of the JCI, Lu et al. identified a pathway involving SEC16B, showing that this protein functions as a lipid-responsive regulator and mediates VLDL secretion and LD formation to maintain lipid homeostasis. They also demonstrated that a reduction in SEC16B reduced serum lipid levels and atherosclerotic plaque area in Ldlr-/- mice. These results indicate that SEC16B connects VLDL and LD metabolism, positioning SEC16B as a potential therapeutic avenue for atherosclerosis.