biostudies-literatureElhan HSwiss National Science FoundationNIDDK NIH HHSNIGMS NIH HHS2601-2613https://www.ebi.ac.uk/biostudies/studies/S-EPMC12700830biostudies-literatureUnknown32(12)Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD expNature structural & molecular biologyATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth.PMC12700830R01 GM100930219264310030F31 DK136246Thiam ARKorfhage JLMelia TJElhan HDamm AZouiouich MGiordano FVanni SAlvarez DfalseATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth.Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD exp2025-01-01T00:00:00Z2025 Dec2026-07-15T06:06:14.492Z2026-07-01T03:07:28.977ZS-EPMC127008304124981910.1038/s41594-025-01689-0