DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.

Hereditary spastic paraplegia subtype SPG54 is a genetic neurological disorder caused by mutations in the DDHD2 gene. Excessive lipid droplet accumulation is observed in the brains of SPG54 patients and DDHD2 knockout mice, consistent with DDHD2's reported neutral lipase activity. Here, we find recombinant human DDHD2 preferentially hydrolyzes diacylglycerol (DAG) over phospholipids, with a slight preference for DAG over triacylglycerol (TAG). DDHD2 also exhibits transacylase activity, which enables transfer of acyl chains from triacylglycerols to diacylglycerols and monoacylglycerols to remodel the acyl chains of triglycerides. A predicted hydrophobic amphipathic helix on DDHD2 is essential for lipid droplet binding in vitro and in cells, and its lack reduces the enzymatic activity and triglyceride acyl chain remodeling. Adipose triglyceride lipase (ATGL), but not hormone sensitive lipase (HSL), also has transacylation activity and can remodel triglyceride acyl chains, but to a lesser extent than DDHD2. Taken together, this provides evidence that DDHD2 is a neutral lipid lipase and transacylase whose broad specificity enables triglyceride acyl-chain remodeling.