α/β Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal/Lysosomal Lipid Bis(monoacylglycero)phosphate

Pribasnig, Maria A.; Mrak, Irina; Grabner, G; Taschler, Ulrike; Knittelfelder, Oskar; Scherz, Barbara; Eichmann, Thomas O.; Heier, Christoph; Grumet, Lukas; Kowaliuk, Jakob; Romauch, Matthias; Höller, Stefan; Anderl, Felix; Wolinski, Heimo; Lass, Achim; Breinbauer, Rolf; Marsche, Gunther; Brown, J. Mark; Zimmermann, R.

doi:10.1074/jbc.m115.669168

Cited by 45 publications

(54 citation statements)

References 52 publications

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“…16:0 LysoPG and 18:1 lysoPG levels were increased at 24 h but not at 6 h after treatment. This is in accordance with recent findings that suggest a lower velocity for lysoPG than for monoacylglycerol hydrolysis by ABHD6 (36). Although MAGL has never been described as a lysophospholipase, we also show variations in the levels of some lysophospholipids in the alveolar space (but not in the lungs) 24 h after JZL184 administration.…”

Section: Discussionsupporting

confidence: 93%

The α/β–hydrolase domain 6 inhibitor WWL70 decreases endotoxin‐induced lung inflammation in mice, potential contribution of 2‐arachidonoylglycerol, and lysoglycerophospholipids

et al. 2019

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Lung inflammation plays a crucial role in the pathogenesis of many respiratory diseases that are in need of new therapeutic strategies. Previously, we showed that inhibition of α/β–hydrolase domain 6 (ABHD6) decreased macrophage activation and exerted anti‐inflammatory effects. Therefore, we thought to assess the effects of ABHD6 inhibition in a mouse model of acute lung injury (ALI) induced by intratracheal administration of lipopolysaccharides. ABHD6 inhibition with N‐methyl‐N‐{[3‐(4‐pyridinyl)phenyl]methyl}‐carbamic acid 4′‐(aminocarbonyl)(l,1′‐biphenyl)‐4‐yl ester (WWL70) decreases most of the hallmarks of ALI, including neutrophil infiltration, cytokine secretion, and protein extravasation. mRNA expression of proinflammatory markers in the cells recovered in the bronchoalveolar lavage was also decreased. Interestingly, ABHD6 inhibition was more efficient than monoacylglycerol lipase inhibition by 4‐nitrophenyl‐4‐[dibenzo(d)(14)dioxol‐5‐yl(hydroxy)methyl]piperidine‐1‐carboxylate. We also studied ABHD6 inhibition on primary alveolar macrophages and neutrophils to explore their potential implication in the effects of ABHD6 inhibition in vivo. Moreover, we quantified by high‐performance liquid chromatography–mass spectrometry the levels of reported substrates of ABHD6 [i.e., 2‐arachidonoylglycerol (2‐AG) and lysophospholipids]. The potential implication of these lipid mediators in the effects of WWL70 was further investigated on primary alveolar macrophages. Taken together, these data support ABHD6 inhibition as an interesting anti‐inflammatory strategy in acute lung inflammation and assess the possible contribution of 2‐AG and lysophospholipids in the observed effects.—Bottemanne, P., Paquot, A., Ameraoui, H., Alhouayek, M., Muccioli, G. G. The α/β–hydrolase domain 6 inhibitor WWL70 decreases endotoxin‐induced lung inflammation in mice, potential contribution of 2‐arachidonoylglycerol, and lysoglycerophospholipids. FASEB J. 33, 7635–7646 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

The α/β–hydrolase domain 6 inhibitor WWL70 decreases endotoxin‐induced lung inflammation in mice, potential contribution of 2‐arachidonoylglycerol, and lysoglycerophospholipids

et al. 2019

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“…Our proof-of-principle application identified the lipase ABHD6 as a regulator of metastatic seeding of PDAC. In the nervous system, ABHD6 modulates endocannabinoid signaling, however, ABHD6 is expressed in many cell types where it has different lipid substrates 35,37,38 . A similar enzyme, MAGL, contributes to a pathogenic lipid signature in cancer 39,40 and high ABHD6 expression correlates with increased metastatic ability in some cancer 41 .…”

Section: Discussionmentioning

confidence: 99%

An in vivo multiplexed small-molecule screening platform

et al. 2016

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Phenotype-based small molecule screening is a powerful method to identify regulators of cellular function. However, such screens are generally performed in vitro using conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of libraries of small molecules. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed towards hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.

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“…This lipid is found in intraluminalv esicles of late endosomes and lysosomes, where it is required for efficient degradation ands orting of lipids. [108] Medical relevance:S elective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-DIO,h epatic steatosis, and systemic insulin resistance. [109] Accordingly,i nhibitors might serve as therapeuticsf or obesity,n onalcoholic fatty liver disease, and type II diabetes.…”

Section: 332d Dhd-domain-containing 2lipase (Ddhd2)mentioning

confidence: 99%

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

et al. 2016

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The coordinated processes of lipid synthesis, degradation, and transport are mediated by enzymes, cofactors, and transport proteins. Accordingly, lipid-metabolizing enzymes represent logical targets for the treatment of dyslipidemia, a major risk factor for type 2 diabetes, atherosclerosis, and other disorders. Small-molecule tool compounds, modulating the functions of such proteins, can substantially facilitate the characterization of target proteins. Such molecules complement genetic studies, and allow time- and dose-dependent control of protein activity in biological systems. This can improve our understanding of physiological processes, give insights into the druggability of target proteins, and might finally result in the development of therapeutic compounds. In this review we summarize the current state of available inhibitors targeting key proteins in neutral lipid metabolism, with a focus on metabolic lipases, acyltransferases, and fatty-acid-binding proteins.

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α/β Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal/Lysosomal Lipid Bis(monoacylglycero)phosphate

Cited by 45 publications

References 52 publications

The α/β–hydrolase domain 6 inhibitor WWL70 decreases endotoxin‐induced lung inflammation in mice, potential contribution of 2‐arachidonoylglycerol, and lysoglycerophospholipids

The α/β–hydrolase domain 6 inhibitor WWL70 decreases endotoxin‐induced lung inflammation in mice, potential contribution of 2‐arachidonoylglycerol, and lysoglycerophospholipids

An in vivo multiplexed small-molecule screening platform

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

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