Xu et al. describe how two lipid-modifying enzymes form a complex that links the endoplasmic reticulum (ER) to lipid droplets in order to promote triglyceride synthesis and storage.

Cells store excess fatty acids inside lipid droplets. These organelles consist of a neutral triglyceride core surrounded by a phospholipid monolayer and are closely associated with ER cisternae. How and why the ER contacts lipid droplets is unclear, however.

Xu et al. screened for C. elegans mutants that suppressed the formation of large lipid droplets in a strain with elevated fatty acid levels. Two enzymes involved in triglyceride synthesis were required for lipid droplet expansion: an acyl-CoA synthetase called FATP1 and the diacylglycerol acyl-transferase DGAT2. FATP1 localized to the ER, whereas DGAT2 resided on lipid droplets. Nevertheless, the two enzymes formed a complex in vivo that concentrated at the interface between their respective organelles, and mislocalizing DGAT2 to the ER prevented it from promoting lipid droplet expansion.

The two proteins behaved similarly in mammalian cells loaded with excess fatty acids, suggesting that they have a conserved function in linking the ER to lipid droplets and channeling newly synthesized triglycerides to the lipid droplet core. Senior author Ho Yi Mak now wants to investigate whether the FATP1–DGAT2 complex contains additional enzymes involved in triglyceride synthesis and to determine whether formation of the complex is regulated by nutrient availability.