Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL.

Autor:	Hofer P; Institute of Molecular Biosciences, University of Graz, Graz, Austria., Grabner GF; Institute of Molecular Biosciences, University of Graz, Graz, Austria., König M; Institute of Molecular Biosciences, University of Graz, Graz, Austria., Xie H; Institute of Molecular Biosciences, University of Graz, Graz, Austria; State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China., Bulfon D; Institute of Molecular Biosciences, University of Graz, Graz, Austria., Ludwig AE; Institute of Molecular Biosciences, University of Graz, Graz, Austria., Wolinski H; Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria., Zimmermann R; Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria., Zechner R; Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria., Heier C; Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria. Electronic address: christoph.heier@uni-graz.at.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2023 Nov; Vol. 64 (11), pp. 100457. Date of Electronic Publication: 2023 Oct 11.
DOI:	10.1016/j.jlr.2023.100457
Abstrakt:	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. Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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