Autophagy regulates lipid metabolism. This study reveals a previously unknown function of autophagy in regulating intracellular lipid stores, termed macrolipophagy. During nutrient deprivation, autophagy delivers intracellular lipids, including those stored in lipid droplets (LDs), to lysosomes for degradation. Inhibition of autophagy in hepatocytes and mouse liver increases triglyceride (TG) storage in LDs. Autophagy and lipolysis share regulatory and functional similarities, but their relationship was previously unclear. The study shows that autophagy is required for LD breakdown, as evidenced by increased TG levels and LD accumulation when autophagy is inhibited. Autophagy components associate with LDs, and inhibition of autophagy reduces the delivery of LD content to lysosomes. Electron microscopy and immunogold labeling confirmed that LDs are engulfed by autophagosomes, which then fuse with lysosomes. The study also demonstrates that autophagy is involved in the regulation of hepatic lipid stores in vivo. In mice with a hepatocyte-specific knockout of the autophagy gene Atg7, there was increased lipid accumulation, including higher levels of TGs, cholesterol, and LD-associated proteins. These findings suggest that autophagy plays a critical role in lipid metabolism, and its dysfunction may contribute to lipid over-accumulation in diseases such as those associated with the metabolic syndrome. The study highlights the importance of autophagy in maintaining cellular energy homeostasis by regulating lipid storage and degradation.Autophagy regulates lipid metabolism. This study reveals a previously unknown function of autophagy in regulating intracellular lipid stores, termed macrolipophagy. During nutrient deprivation, autophagy delivers intracellular lipids, including those stored in lipid droplets (LDs), to lysosomes for degradation. Inhibition of autophagy in hepatocytes and mouse liver increases triglyceride (TG) storage in LDs. Autophagy and lipolysis share regulatory and functional similarities, but their relationship was previously unclear. The study shows that autophagy is required for LD breakdown, as evidenced by increased TG levels and LD accumulation when autophagy is inhibited. Autophagy components associate with LDs, and inhibition of autophagy reduces the delivery of LD content to lysosomes. Electron microscopy and immunogold labeling confirmed that LDs are engulfed by autophagosomes, which then fuse with lysosomes. The study also demonstrates that autophagy is involved in the regulation of hepatic lipid stores in vivo. In mice with a hepatocyte-specific knockout of the autophagy gene Atg7, there was increased lipid accumulation, including higher levels of TGs, cholesterol, and LD-associated proteins. These findings suggest that autophagy plays a critical role in lipid metabolism, and its dysfunction may contribute to lipid over-accumulation in diseases such as those associated with the metabolic syndrome. The study highlights the importance of autophagy in maintaining cellular energy homeostasis by regulating lipid storage and degradation.