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PreprintCited by 3Lipid metabolism and biosynthesisLipid metabolism and disordersSphingolipid Metabolism and Signaling

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

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Wu, Lingshuang, Choi, Yong Mi, Omrane, Mohyeddine, Chai, Jiyao, Gao, Shujuan, Thiam, Abdou Rachid, Canals, Daniel, Airola, Michael V.·2025·Proceedings of the National Academy of Sciences
DOI 10.1101/2025.09.22.677815PMC PMC12485780

Preprint — published as 10.1073/pnas.2500527122

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Abstract

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. SIGNIFICANCE STATEMENT: Triglycerides (TAGs), the primary form of long-term energy storage, have acyl chain compositions crucial for diverse cellular processes. Lipases typically hydrolyze TAGs into free fatty acids. Here, we reveal a novel function for the neutral lipid lipase DDHD2: a transacylase activity. Instead of releasing fatty acids, DDHD2 transfers them between neutral lipids, altering TAG acyl chain composition. This transacylation requires the unique oil environment of lipid droplets (LDs), which excludes water from DDHD2’s lipolytic active site, favoring transacylation over hydrolysis. DDHD2’s lipase and transacylase activities enable TAG acyl-chain remodeling, demonstrating the possibility that a single enzyme can catalyze TAG cycling. This finding has implications for understanding lipid metabolism, LD dynamics, and specific motor neuron diseases implicating DDHD2.

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Metadata

Authors
Wu, L., Choi, Y. M., Omrane, M., Chai, J., Gao, S., Thiam, A. R., Canals, D., & Airola, M. V.
Affiliations
  • Stony Brook University (US)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Canals, Daniel
  • Airola, Michael V.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2025-09-22
Volume
122
Issue
47
Pages
e2500527122-e2500527122
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2025.09.22.677815
PMC
PMC12485780
OpenAlex
W4416424415
Cited by
3
References
1
Citations by year
2026: 2 · 2025: 1
FWCI
0.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • HAL (submittedVersion, other-oa)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
Funders
  • NIH (R35GM128666)
  • Stony Brook Cancer Center
  • American Heart Association (23PRE1019634)
  • Agence Nationale de la Recherche (ANR-21-CE13-0014-LIPDROPER)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords
DDHD2, hereditary spastic paraplegia, neutral lipase, acyltransferase, lipid droplet accumulation, amphipathic helix, adipose triglyceride lipase, hormone-sensitive lipase, monoglycerides, triglycerides

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