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Inhibition of diacylglycerol lipase β modulates lipid and endocannabinoid levels in the ex vivo human placenta

ABSTRACT: This study utilized MS-based activity-based protein profiling to generate an activity landscape of placental catalytically active serine hydrolases, aiming to investigate the main 2-AGbiosynthetic enzyme in the human placenta

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Placenta

SUBMITTER: Natascha Berger

LAB HEAD: Christian Wadsack

PROVIDER: PXD039930 | Pride | 2023-03-10

REPOSITORIES: pride

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	210923_NB_Cyt_01.raw	Raw
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Inhibition of diacylglycerol lipase β modulates lipid and endocannabinoid levels in the <i>ex vivo</i> human placenta.

Berger Natascha N van der Wel Tom T Hirschmugl Birgit B Baernthaler Thomas T Gindlhuber Juergen J Fawzy Nermeen N Eichmann Thomas T Birner-Gruenberger Ruth R Zimmermann Robert R van der Stelt Mario M Wadsack Christian C

Frontiers in endocrinology 20230214

<h4>Introduction</h4>Lipids and fatty acids are key components in metabolic processes of the human placenta, thereby contributing to the development of the fetus. Placental dyslipidemia and aberrant activity of lipases have been linked to diverse pregnancy associated complications, such as preeclampsia and preterm birth. The serine hydrolases, diacylglycerol lipase α and β (DAGLα, DAGLβ) catalyze the degradation of diacylglycerols, leading to the formation of monoacylglycerols (MAG), including o ...[more]

PMID: 36864832

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CaMKII regulates diacylglycerol lipase-? and striatal endocannabinoid signaling.

Project description:The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates activity-dependent depression of excitatory neurotransmission at central synapses, but the molecular regulation of 2-AG synthesis is not well understood. Here we identify a functional interaction between the 2-AG synthetic enzyme diacylglycerol lipase-? (DGL?) and calcium/calmodulin dependent protein kinase II (CaMKII). Activated CaMKII interacted with the C-terminal domain of DGL?, phosphorylated two serine residues and inhibited DGL? activity. Consistent with an inhibitory role for CaMKII in 2-AG synthesis, in vivo genetic inhibition of CaMKII increased striatal DGL activity and basal levels of 2-AG, and CaMKII inhibition augmented short-term retrograde endocannabinoid signaling at striatal glutamatergic synapses. Lastly, blockade of 2-AG breakdown using concentrations of JZL-184 that have no effect in wild-type mice produced a hypolocomotor response in mice with reduced CaMKII activity. These findings provide mechanistic insights into the molecular regulation of striatal endocannabinoid signaling with implications for physiological control of motor function.

| S-EPMC3636998 | biostudies-literature

Diacylglycerol lipase ? manipulation reveals developmental roles for intercellular endocannabinoid signaling.

Project description:Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacylglycerol lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB? cannabinoid receptors (CB?Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGL? null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGL? overexpression spherically excludes cholinergic growth cones from 2-AG-rich extracellular environments, and minimizes cell-cell contact in vitro. CB?R-mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB?Rs along discrete spherical boundaries to modulate neuronal responsiveness.

| S-EPMC3695556 | biostudies-literature

RNA-seq of mouse small intestinal CCR6+ group3 innate lymphoid cells

Project description:CCR6+NKp46- ILC3 were isolated from the small intestine of untreated mice by flow cytometry. ILC3 from 3 mice were pooled for subsequent RNA sequencing.

2019-10-11 | E-MTAB-8387 | biostudies-arrayexpress

Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system.

Project description:Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

| S-EPMC2928870 | biostudies-literature

Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice.

Project description:BACKGROUND & AIMS:The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. METHODS:We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll(-/-) mice, fatty acid amide hydrolase(-/-) mice, and in cannabinoid receptor type 1(-/-) (CB1-/-) and cannabinoid receptor type 2(-/-) (CB2-/-). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. RESULTS:Wild-type mice given JZL184 and Mgll(-/-) mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB2 and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl4. CONCLUSIONS:MAGL modulates hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat conditions that expose the liver to oxidative stress and inflammatory damage.

| S-EPMC3608818 | biostudies-literature

First identification of Cr-binding proteome in human HepG2 cells

Project description:By integrating fluorescence imaging with proteomic approach, we visualized Cr3+ protein targets mainly localized in mitochondria and identified eight Cr3+-binding proteins, including ATP synthase catalytic subunit beta (ATP5B).

2023-05-10 | PXD027305 | Pride

Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.

Project description:Monoacylglycerol lipase (MAGL) is a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). We recently reported a piperidine carbamate, JZL184, that inhibits MAGL with high potency and selectivity. Here, we describe a comprehensive mechanistic characterization of JZL184. We provide evidence that JZL184 irreversibly inhibits MAGL via carbamoylation of the enzyme's serine nucleophile. Functional proteomic analysis of mice treated with JZL184 revealed that this inhibitor maintains good selectivity for MAGL across a wide range of central and peripheral tissues. Interestingly, MAGL blockade produced marked, tissue-specific differences in monoglyceride metabolism, with brain showing the most dramatic elevations in 2-AG and peripheral tissues often showing greater changes in other monoglycerides. Collectively, these studies indicate that MAGL exerts tissue-dependent control over endocannabinoid and monoglyceride metabolism and designate JZL184 as a selective tool to characterize the functions of MAGL in vivo.

| S-EPMC2867454 | biostudies-literature

Regulation of adult neurogenesis by the endocannabinoid-producing enzyme diacylglycerol lipase alpha (DAGLa).

Project description:The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.

| S-EPMC8755832 | biostudies-literature

Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice.

Project description:Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol and fatty acid. MGL also hydrolyzes and thereby deactivates 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) and CB2R, which are mainly expressed in brain and immune cells, respectively. Thus, we speculated that in the absence of MGL, increased 2-AG concentrations mediate CB2R signaling in immune cells to modulate inflammatory responses, thereby affecting the development of atherosclerosis.We generated apolipoprotein E (ApoE)/MGL double-knockout (DKO) mice and challenged them with Western-type diet for 9 weeks. Despite systemically increased 2-AG concentrations in DKO mice, CB2R-mediated signaling remains fully functional, arguing against CB2R desensitization. We found increased plaque formation in both en face aortae (1.3-fold, p = 0.028) and aortic valve sections (1.5-fold, p = 0.0010) in DKO mice. Interestingly, DKO mice also presented reduced lipid (12%, p = 0.031) and macrophage content (18%, p = 0.061), elevated intraplaque smooth muscle staining (1.4-fold, p = 0.016) and thicker fibrous caps (1.8-fold, p = 0.0032), together with a higher ratio of collagen to necrotic core area (2.5-fold, p = 0.0003) and expanded collagen content (1.6-fold, p = 0.0007), which suggest formation of less vulnerable atherosclerotic plaques. Treatment with a CB2R inverse agonist prevents these effects in DKO mice, demonstrating that the observed plaque phenotype in DKO mice originates from CB2R activation.Loss of MGL modulates endocannabinoid signaling in CB2R-expressing cells, which concomitantly affects the pathogenesis of atherosclerosis. We conclude that despite larger lesion size loss of MGL improves atherosclerotic plaque stability. Thus, pharmacological MGL inhibition may be a novel intervention to reduce plaque rupture.

| S-EPMC4704137 | biostudies-literature

Regulatory role of multinucleated giant cells derived from placental CD14+ macrophages: Pathophysiological implications

Project description:The role of placental macrophages is largely ignored in the success of pregnancy. We found that CD14+ macrophages purified from at-term placentas spontaneously matured into multinucleated giant cells (MGCs). MGCs lost the expression of CD14 and co-inhibitory molecules, such as Programmed cell Death-Ligands 1 and 2. Although MGCs kept phagocytosis and property to produce ROS, their inflammatory potential measured by TNF/IL-10 imbalance and activation of p38 MAPK and NF-M-NM-:B was blunted without being associated with M2 phenotype. The investigation of gene expression revealed the enrichment with categories related to inflammation, apoptosis and canonical functions of macrophages in MGCs. Whereas most of the genes associated with inflammation and immune responses were down-modulated, those such as VEGFC or associated with matrix remodeling were specifically up-regulated in MGCs. Importantly, we found that patients with preeclampsia or chorioamnionitis, two inflammatory and infectious pathologies, respectively, that affect placentas, were unable to generate MGCs. Taken together, these results suggest that MGCs represent a new way to regulate the inflammatory and cytocidal activity of placental macrophages in a context that imposes contradictory constraints, such as semi-allograft acceptance and defense against aggression. The dysregulation of MGC formation may be associated with placental inflammatory and infectious pathologies. Placental macrophages CD14+ were cultured for 9 days to form multinucleated giant cells (MGC). The transcriptome of MGCs was compared to the transcriptome of placental macrophages (CD14+)

2014-01-07 | E-GEOD-38747 | biostudies-arrayexpress