Dataset Information

Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice

ABSTRACT: N‑acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as the first CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.

INSTRUMENT(S): SYNAPT G2-Si

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Bogdan Florea

LAB HEAD: Mario van der Stelt

PROVIDER: PXD017586 | Pride | 2020-05-15

REPOSITORIES: Pride

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			Action	DRS
	20180219_EM_Hek_71117_01.raw	Raw
	20180219_EM_Hek_71117_02.raw	Raw
	20180219_EM_Hek_71117_03.raw	Raw
	20180219_EM_Hek_71117_04.raw	Raw
	20180219_EM_Hek_71117_05.raw	Raw

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Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice.

Mock Elliot D ED Mustafa Mohammed M Gunduz-Cinar Ozge O Cinar Resat R Petrie Gavin N GN Kantae Vasudev V Di Xinyu X Ogasawara Daisuke D Varga Zoltan V ZV Paloczi Janos J Miliano Cristina C Donvito Giulia G van Esbroeck Annelot C M ACM van der Gracht Anouk M F AMF Kotsogianni Ioli I Park Joshua K JK Martella Andrea A van der Wel Tom T Soethoudt Marjolein M Jiang Ming M Wendel Tiemen J TJ Janssen Antonius P A APA Bakker Alexander T AT Donovan Colleen M CM Castillo Laura I LI Florea Bogdan I BI Wat Jesse J van den Hurk Helma H Wittwer Matthias M Grether Uwe U Holmes Andrew A van Boeckel Constant A A CAA Hankemeier Thomas T Cravatt Benjamin F BF Buczynski Matthew W MW Hill Matthew N MN Pacher Pal P Lichtman Aron H AH van der Stelt Mario M

Nature chemical biology 20200511 6

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibito ...[more]

PMID: 32393901

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Project description:A time course of the effect of overexpressing GPI-PLD on global gene expression in HepG2 cells was compared to control virus. Experiment Overall Design: This experiment compares the global gene expression in HepG2 cells that were either transduced with an adenovirus expressing GPI-phospholipase D or an adenovirus expressing beta galactosidase as a control. Treatment was for 6 or 12 hrs. Four replicates for each condition were used. 10 micrograms of total RNA was assayed per genechip using standard Affymetrix protocols. CONTEXT: Recent studies demonstrated that de novo lipogenesis is increased in patients with nonalcoholic fatty liver disease (NAFLD). Patients with NAFLD also have plasma lipid abnormalities. These lipid abnormalities may in part be related to insulin resistance, which is common in patients with NAFLD. Insulin resistance is associated with alterations in proteins involved in lipid metabolism including glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), which is involved in triglyceride metabolism. OBJECTIVE: The objective of the study was to determine whether alterations in serum and hepatic levels of GPI-PLD occur in patients with NAFLD. DESIGN AND PATIENTS: We examined the following: 1) levels of serum GPI-PLD in nondiabetics with nonalcoholic steatohepatitis, compared with matched controls; 2) hepatic expression of GPI-PLD mRNA in patients with normal liver or NAFLD; and 3) effect of overexpressing GPI-PLD vs. beta-galactosidase (control) on global gene expression in a human hepatoma cell line. RESULTS: The serum levels of GPI-PLD were significantly higher in patients with nonalcoholic steatohepatitis than in matched controls (119 +/- 24 vs.105 +/- 15 microg/ml, P = 0.047). The hepatic expression of GPI-PLD mRNA was increased nearly 3-fold in NAFLD patients, compared with patients with normal liver (3.1 +/- 2.6 vs. 1.1 +/- 1.0 arbitrary units per microgram total RNA, P = 0.026). Finally, overexpressing GPI-PLD was associated with an increase in de novo lipogenesis genes. CONCLUSIONS: Patients with NAFLD have elevated serum levels and hepatic expression of GPI-PLD, and its overexpression in vitro is associated with increased expression of de novo lipogenesis genes. These results suggest that GPI-PLD may play a role in the pathogenesis of NAFLD and/or its metabolic features and warrants further investigation.