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Hofer, P; Grabner, GF; König, M; Xie, H; Bulfon, D; Ludwig, AE; Wolinski, H; Zimmermann, R; Zechner, R; Heier, C.
Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL.
J Lipid Res. 2023; 64(11): 100457 Doi: 10.1016/j.jlr.2023.100457 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Grabner Gernot
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Abstract:
Intracellular lipolysis-the enzymatic breakdown of lipid droplet-associated triacylglycerol (TAG)-depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independently of ATGL via DDHD domain-containing 2 (DDHD2), a multifunctional lipid hydrolase whose dysfunction causes neuronal TAG deposition and hereditary spastic paraplegia. Whether and how DDHD2 cooperates with other lipolytic enzymes is currently unknown. In this study, we further investigated the enzymatic properties and functions of DDHD2 in neuroblastoma cells and primary neurons. We found that DDHD2 hydrolyzes multiple acylglycerols in vitro and substantially contributes to neutral lipid hydrolase activities of neuroblastoma cells and brain tissue. Substrate promiscuity of DDHD2 allowed its engagement at different steps of the lipolytic cascade: In neuroblastoma cells, DDHD2 functioned exclusively downstream of ATGL in the hydrolysis of sn-1,3-diacylglycerol (DAG) isomers but was dispensable for TAG hydrolysis and lipid droplet homeostasis. In primary cortical neurons, DDHD2 exhibited lipolytic control over both, DAG and TAG, and complemented ATGL-dependent TAG hydrolysis. We conclude that neuronal cells use noncanonical configurations of the lipolysome and engage DDHD2 as dual TAG/DAG hydrolase in cooperation with ATGL.
Find related publications in this database (using NLM MeSH Indexing)
Humans - administration & dosage
Lipase - genetics, metabolism
Lipolysis - administration & dosage
Neurons - metabolism
Paraplegia - administration & dosage
Phospholipases - metabolism
Triglycerides - metabolism

Find related publications in this database (Keywords)
Lipolysis and fatty acid metabolism
brain lipids
enzymology
lipase
triacylglycerol
lipid droplets
neurons
spastic paraplegia
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