Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also directly regulate systemic cellular activities, remains unknown. Here, we report the ultrastructural organization and dynamics of a new type of inter-organelle contact which is formed by rough-Endoplasmic Reticulum that is closely wrapped around the mitochondrion (wrappER). To elucidate the in vivo function of this inter-organelle association, mouse liver fractions enriched in wrappER-associated-mitochondria were analyzed in parallel by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to an unexpected role in the biogenesis of very-low-density lipoproteins (VLDLs). Altering wrappER-mitochondria contacts curtails liver VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, mirrors this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The participation of liver wrappER-mitochondria contacts in VLDL biology reveals a role of inter-organelle contacts in systemic lipid homeostasis.